Wang P, Deng J, Dong J, Liu J, Bigio EH, Mesulam M, Wang T, Sun L, Wang L, Lee AY, McGee WA, Chen X, Fushimi K, Zhu L, Wu JY. TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genet. 2019 May 17;15(5):e1007947. PubMed PMID: 31100073; PubMed Central PMCID: PMC6524796.
From the abstract: "Mutations in or dys-regulation of the TDP-43 gene have been associated with TDP-43 proteinopathy, a spectrum of neurodegenerative diseases including Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). The underlying molecular and cellular defects, however, remain unclear. Here, we report a systematic study combining analyses of patient brain samples with cellular and animal models for TDP-43 proteinopathy. ... Our work has not only uncovered a previously unknown role of LonP1 in regulating mitochondrial TDP-43 levels, but also advanced our understanding of the pathogenic mechanisms for TDP-43 proteinopathy. Our study suggests that blocking or reversing mitochondrial damage may provide a potential therapeutic approach to these devastating diseases."
Bogaert E, Boeynaems S, Kato M, Guo L, Caulfield TR, Steyaert J, Scheveneels W, Wilmans N, Haeck W, Hersmus N, Schymkowitz J, Rousseau F, Shorter J, Callaerts P, Robberecht W, Van Damme P, Van Den Bosch L. Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity. Cell Rep. 2018 Jul 17;24(3):529-537.e4. PubMed PMID: 30021151; PubMed Central PMCID: PMC6077250.
Abstract: "RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity and identified a previously unrecognized synergistic effect between the N-terminal prion-like domain and the C-terminal arginine-rich domain to mediate toxicity. Although the prion-like domain is generally considered to mediate aggregation of FUS, we find that arginine residues in the C-terminal low-complexity domain are also required for maturation of FUS in cellular stress granules. These data highlight an important role for arginine-rich domains in the pathology of RNA-binding proteins."
Showing posts with label Frontotemporal lobar dementia. Show all posts
Showing posts with label Frontotemporal lobar dementia. Show all posts
Wednesday, December 4, 2019
Tuesday, June 25, 2019
Fly model of FTD used to identify compound reported to reduce toxic phosphorylated tau
Shim KH, Kim SH, Hur J, Kim DH, Demirev AV, Yoon SY. Small-molecule drug screening identifies drug Ro 31-8220 that reduces toxic phosphorylated tau in Drosophila melanogaster. Neurobiol Dis. 2019 Jun 21:104519. doi: 10.1016/j.nbd.2019.104519. PMID: 31233882.
Abstract: "The intraneuronal aggregates of hyperphosphorylated and misfolded tau (neurofibrillary tangles, NFTs) cause a stereotypical spatiotemporal Alzheimer's disease (AD) progression that correlates with the severity of the associated cognitive decline. Kinase activity contributes to the balance between neuron survival and cell death. Hyperactivation of kinases including the conventional protein kinase C (PKC) is a defective molecular event accompanying associative memory loss, tau phosphorylation, and progression of AD or related neurodegenerative diseases. Here, we investigated the ability of small therapeutic compounds (a custom library) to improve tau-induced rough-eye phenotype in a Drosophila melanogaster model of frontotemporal dementia. We also assessed the tau phosphorylation in vivo and selected hit compounds. Among the potential hits, we investigated Ro 31-8220, described earlier as a potent PKCα inhibitor. Ro 31-8220 robustly improved the rough-eye phenotype, reduced phosphorylated tau species in vitro and in vivo, reversed tau-induced memory impairment, and improved the fly motor functions. In a human neuroblastoma cell line, Ro 31-8220 reduced the PKC activity and the tau phosphorylation pattern, but we also have to acknowledge the compound's wide range of biological activity. Nevertheless, Ro 31-8220 is a novel therapeutic mitigator of tau-induced neurotoxocity."
Abstract: "The intraneuronal aggregates of hyperphosphorylated and misfolded tau (neurofibrillary tangles, NFTs) cause a stereotypical spatiotemporal Alzheimer's disease (AD) progression that correlates with the severity of the associated cognitive decline. Kinase activity contributes to the balance between neuron survival and cell death. Hyperactivation of kinases including the conventional protein kinase C (PKC) is a defective molecular event accompanying associative memory loss, tau phosphorylation, and progression of AD or related neurodegenerative diseases. Here, we investigated the ability of small therapeutic compounds (a custom library) to improve tau-induced rough-eye phenotype in a Drosophila melanogaster model of frontotemporal dementia. We also assessed the tau phosphorylation in vivo and selected hit compounds. Among the potential hits, we investigated Ro 31-8220, described earlier as a potent PKCα inhibitor. Ro 31-8220 robustly improved the rough-eye phenotype, reduced phosphorylated tau species in vitro and in vivo, reversed tau-induced memory impairment, and improved the fly motor functions. In a human neuroblastoma cell line, Ro 31-8220 reduced the PKC activity and the tau phosphorylation pattern, but we also have to acknowledge the compound's wide range of biological activity. Nevertheless, Ro 31-8220 is a novel therapeutic mitigator of tau-induced neurotoxocity."
Friday, May 24, 2019
Fly studies help provide insights into role of nucleocytoplasmic transport in ALS/FTD
Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG, Chen YH, Duong DM, Seyfried NT, Powers MA, Kukar T, Hales CM, Gearing M, Cairns NJ, Boylan KB, Dickson DW, Rademakers R, Zhang YJ, Petrucelli L, Sattler R, Zarnescu DC, Glass JD, Rossoll W. TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci. 2018 Feb;21(2):228-239. doi: 10.1038/s41593-017-0047-3. Epub 2018 Jan 8. PubMed PMID: 29311743; PubMed Central PMCID: PMC5800968.
Abstract: "The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD."
See also comment in Nature Neuroscience.
Abstract: "The cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a common histopathological hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum (ALS/FTD). However, the composition of aggregates and their contribution to the disease process remain unknown. Here we used proximity-dependent biotin identification (BioID) to interrogate the interactome of detergent-insoluble TDP-43 aggregates and found them enriched for components of the nuclear pore complex and nucleocytoplasmic transport machinery. Aggregated and disease-linked mutant TDP-43 triggered the sequestration and/or mislocalization of nucleoporins and transport factors, and interfered with nuclear protein import and RNA export in mouse primary cortical neurons, human fibroblasts and induced pluripotent stem cell-derived neurons. Nuclear pore pathology is present in brain tissue in cases of sporadic ALS and those involving genetic mutations in TARDBP and C9orf72. Our data strongly implicate TDP-43-mediated nucleocytoplasmic transport defects as a common disease mechanism in ALS/FTD."
See also comment in Nature Neuroscience.
Tuesday, April 30, 2019
Autophagy, lysosomes, and ALS/FTD
Şentürk M, Mao D, Bellen HJ. Loss of proteins associated with amyotrophic lateral sclerosis affect lysosomal acidification via different routes. Autophagy. 2019 Apr 28:1-3. PubMed
PMID: 31032688.
Abstract: "Abnormal accumulation of proteins is a hallmark of a variety of neurological diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Maintenance of protein homeostasis (proteostasis) in neurons via proteasomal and macroautophagy/autophagy-lysosomal degradation is thought to be central for proper neuronal function and survival. We recently reported evolutionarily conserved roles for two ALS-linked proteins, UBQLN2 (ubiquilin 2) and VAPB, in regulation of lysosomal degradation. Ubiquilins are required for v-ATPase-mediated lysosomal acidification, whereas VAPs are required for the PtdIns4P-mediated endo-lysosomal trafficking pathway."
PMID: 31032688.
Abstract: "Abnormal accumulation of proteins is a hallmark of a variety of neurological diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Maintenance of protein homeostasis (proteostasis) in neurons via proteasomal and macroautophagy/autophagy-lysosomal degradation is thought to be central for proper neuronal function and survival. We recently reported evolutionarily conserved roles for two ALS-linked proteins, UBQLN2 (ubiquilin 2) and VAPB, in regulation of lysosomal degradation. Ubiquilins are required for v-ATPase-mediated lysosomal acidification, whereas VAPs are required for the PtdIns4P-mediated endo-lysosomal trafficking pathway."
Wednesday, January 30, 2019
Fly model used in drug discovery study related to FTD and ALS (research report now available at PubMed Central)
Simone R, et al. G-quadruplex-binding small molecules ameliorate C9orf72 FTD/ALS pathology in vitro and in vivo. EMBO Mol Med. 2018 Jan;10(1):22-31. doi: 10.15252/emmm.201707850. PubMed PMID: 29113975; PubMed Central PMCID: PMC5760849.
From the abstract: "Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. ... We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA ... Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat-expressing Drosophila ... These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential."
From the abstract: "Intronic GGGGCC repeat expansions in C9orf72 are the most common known cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which are characterised by degeneration of cortical and motor neurons, respectively. ... We performed a screen that identified three structurally related small molecules that specifically stabilise GGGGCC repeat G-quadruplex RNA ... Furthermore, they also reduce dipeptide repeat proteins and improve survival in vivo, in GGGGCC repeat-expressing Drosophila ... These data provide proof of principle that targeting GGGGCC repeat G-quadruplexes has therapeutic potential."
Thursday, July 19, 2018
New fly model of FUS toxicity
Bogaert E, Boeynaems S, Kato M, Guo L, Caulfield TR, Steyaert J, Scheveneels W, Wilmans N, Haeck W, Hersmus N, Schymkowitz J, Rousseau F, Shorter J, Callaerts P, Robberecht W, Van Damme P, Van Den Bosch L. Molecular Dissection of FUS Points at Synergistic Effect of Low-Complexity Domains in Toxicity. Cell Rep. 2018 Jul 17;24(3):529-537.e4. PMID: 30021151.
From the abstract: "RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity ..."
From the abstract: "RNA-binding protein aggregation is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To gain better insight into the molecular interactions underlying this process, we investigated FUS, which is mutated and aggregated in both ALS and FTLD. We generated a Drosophila model of FUS toxicity ..."
Monday, July 9, 2018
Drosophila used in study related to ALS/FTLD
Mordes DA, Prudencio M, Goodman LD, Klim JR, Moccia R, Limone F, Pietilainen O, Chowdhary K, Dickson DW, Rademakers R, Bonini NM, Petrucelli L, Eggan K. Dipeptide repeat proteins activate a heat shock response found in C9ORF72-ALS/FTLD patients. Acta Neuropathol Commun. 2018 Jul 4;6(1):55. PMID: 29973287.
Abstract: "A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration. To better discern which of these mechanisms leads to disease-associated changes in patient brains, we analyzed gene expression data generated from the cortex and cerebellum. We found that transcripts encoding heat shock proteins (HSPs) regulated by the HSF1 transcription factor were significantly induced in C9ORF72-ALS/FTLD patients relative to both sporadic ALS/FTLD cases and controls. Treatment of human neurons with chemically synthesized DPRs was sufficient to activate a similar transcriptional response. Expression of GGGGCC repeats and also poly-GR in the brains of Drosophila lead to the upregulation of HSF1 and the same highly-conserved HSPs. Additionally, HSF1 was a modifier of poly-GR toxicity in Drosophila. Our results suggest that the expression of DPRs are associated with upregulation of HSF1 and activation of a heat shock response in C9ORF72-ALS/FTLD."
Abstract: "A hexanucleotide (GGGGCC) repeat expansion in C9ORF72 is the most common genetic contributor to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Reduced expression of the C9ORF72 gene product has been proposed as a potential contributor to disease pathogenesis. Additionally, repetitive RNAs and dipeptide repeat proteins (DPRs), such as poly-GR, can be produced by this hexanucleotide expansion that disrupt a number of cellular processes, potentially contributing to neural degeneration. To better discern which of these mechanisms leads to disease-associated changes in patient brains, we analyzed gene expression data generated from the cortex and cerebellum. We found that transcripts encoding heat shock proteins (HSPs) regulated by the HSF1 transcription factor were significantly induced in C9ORF72-ALS/FTLD patients relative to both sporadic ALS/FTLD cases and controls. Treatment of human neurons with chemically synthesized DPRs was sufficient to activate a similar transcriptional response. Expression of GGGGCC repeats and also poly-GR in the brains of Drosophila lead to the upregulation of HSF1 and the same highly-conserved HSPs. Additionally, HSF1 was a modifier of poly-GR toxicity in Drosophila. Our results suggest that the expression of DPRs are associated with upregulation of HSF1 and activation of a heat shock response in C9ORF72-ALS/FTLD."
Tuesday, November 21, 2017
Studies "launching from Drosophila models" provide insights into molecular mechanisms of ALS and FTD
Berson A, Sartoris A, Nativio R, Van Deerlin V, Toledo JB, Porta S, Liu S, Chung CY, Garcia BA, Lee VM, Trojanowski JQ, Johnson FB, Berger SL, Bonini NM. TDP-43 Promotes Neurodegeneration by Impairing Chromatin Remodeling. Curr Biol. 2017 Nov 9. pii: S0960-9822(17)31327-1. PMID: 29153328.
The abstract: "Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD)."
The abstract: "Regulation of chromatin structure is critical for brain development and function. However, the involvement of chromatin dynamics in neurodegeneration is less well understood. Here we find, launching from Drosophila models of amyotrophic lateral sclerosis and frontotemporal dementia, that TDP-43 impairs the induction of multiple key stress genes required to protect from disease by reducing the recruitment of the chromatin remodeler Chd1 to chromatin. Chd1 depletion robustly enhances TDP-43-mediated neurodegeneration and promotes the formation of stress granules. Conversely, upregulation of Chd1 restores nucleosomal dynamics, promotes normal induction of protective stress genes, and rescues stress sensitivity of TDP-43-expressing animals. TDP-43-mediated impairments are conserved in mammalian cells, and, importantly, the human ortholog CHD2 physically interacts with TDP-43 and is strikingly reduced in level in temporal cortex of human patient tissue. These findings indicate that TDP-43-mediated neurodegeneration causes impaired chromatin dynamics that prevents appropriate expression of protective genes through compromised function of the chromatin remodeler Chd1/CHD2. Enhancing chromatin dynamics may be a treatment approach to amyotrophic lateral scleorosis (ALS)/frontotemporal dementia (FTD)."
Tuesday, December 27, 2016
Genetic modifier screen with a fly model of ALS/FTD
Boeynaems S, Bogaert E, Michiels E, Gijselinck I, Sieben A, Jovičić A, De Baets G, Scheveneels W, Steyaert J, Cuijt I, Verstrepen KJ, Callaerts P, Rousseau F, Schymkowitz J, Cruts M, Van Broeckhoven C, Van Damme P, Gitler AD, Robbenecht W, Van Den Bosch L. Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci Rep. 2016 Feb 12;6:20877. PMID: 26869068; PMCID: PMC4751451.
From the abstract: "Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). ... We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD."
From the abstract: "Hexanucleotide repeat expansions in C9orf72 are the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) (c9ALS/FTD). ... We performed a modifier screen in Drosophila and discovered a critical role for importins and exportins, Ran-GTP cycle regulators, nuclear pore components, and arginine methylases in mediating DPR toxicity. These findings provide evidence for an important role for nucleocytoplasmic transport in the pathogenic mechanism of c9ALS/FTD."
Thursday, December 15, 2016
Catching up on Drosophila papers related to neurodegenerative disease--research reports and a review
Alzheimer's disease
Liu QF, Lee JH, Kim YM, Lee S, Hong YK, Hwang S, Oh Y, Lee K, Yun HS, Lee IS, Jeon S, Chin YW, Koo BS, Cho KS. In Vivo Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using Drosophila Models of Alzheimer's Disease. Biol Pharm Bull. 2015;38(12):1891-901. PMID: 26458335.
Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ. Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease. Sci Rep. 2015 Nov 4;5:16127. PMID: 26530776; PMCID: PMC4632086.
Kong Y, Wu J, Zhang D, Wan C, Yuan L. The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway. Curr Mol Med. 2015;15(10):980-9. PubMed PMID: 26592243.
Peng F, Zhao Y, Huang X, Chen C, Sun L, Zhuang L, Xue L. Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila. Sci Rep. 2015 Nov 24;5:16816. PMID: 26597721; PMCID: PMC4657023.
Geng J, Xia L, Li W, Zhao C, Dou F. Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. J Alzheimers Dis. 2016;49(4):1161-8. PMID: 26599052; PMCID: PMC4927919.
Haddadi M, Nongthomba U, Jahromi SR, Ramesh SR. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration. Behav Brain Res. 2016 Mar 15;301:10-8. PMID: 26706888.
Wang X, Ma Y, Zhao Y, Chen Y, Hu Y, Chen C, Shao Y, Xue L. APLP1 promotes dFoxO-dependent cell death in Drosophila. Apoptosis. 2015 Jun;20(6):778-86. PMID: 25740230.
Lau HC, Lee IK, Ko PW, Lee HW, Huh JS, Cho WJ, Lim JO. Non-invasive screening for Alzheimer's disease by sensing salivary sugar using Drosophila cells expressing gustatory receptor (Gr5a) immobilized on an extended gate ion-sensitive field-effect transistor (EG-ISFET) biosensor. PLoS One. 2015 Feb 25;10(2):e0117810. PMID: 25714733; PMCID: PMC4340960.
Frenkel-Pinter M, Tal S, Scherzer-Attali R, Abu-Hussien M, Alyagor I, Eisenbaum T, Gazit E, Segal D. Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity. J Alzheimers Dis. 2016;51(1):165-78. PMID: 26836184.
ALS
Chai A, Pennetta G. Insights into ALS pathomechanisms: from flies to humans. Fly (Austin). 2015;9(2):91-8. PMID: 26594942; PMCID: PMC4826116. ---REVIEW
Cragnaz L, Klima R, De Conti L, Romano G, Feiguin F, Buratti E, Baralle M, Baralle FE. An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. Neuroscience. 2015 Dec 17;311:415-21. PMID: 26518462.
Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016 Jan 18;35(2):121-42. PMID: 26702100; PMCID: PMC4718457.
Romano M, Feiguin F, Buratti E. TBPH/TDP-43 modulates translation of Drosophila futsch mRNA through an UG-rich sequence within its 5'UTR. Brain Res. 2016 Sep 15;1647:50-6. doi: 10.1016/j.brainres.2016.02.022. PubMed PMID: 26902497.
FTD/ALS
Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao FB. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron. 2015 Sep 23;87(6):1207-14. PMID: 26402604; PMCID: PMC4589299.
Parkinson's disease
West RJ, Elliott CJ, Wade AR. Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. Sci Rep. 2015 Nov 24;5:16933. PMID: 26597171; PMCID: PMC4657034.
Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015 May 1;24(9):2528-38. PMID: 25612572.
Vos M, Verstreken P, Klein C. Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction. Biochem Soc Trans. 2015 Apr;43(2):275-9. PMID: 25849929.
Wiemerslage L, Lee D. Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters. J Neurosci Methods. 2016 Mar 15;262:56-65. PMID: 26777473; PMCID: PMC4775301. ---PROTOCOL
Langston RG, Rudenko IN, Cookson MR. The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research. Biochem J. 2016 Feb 1;473(3):221-32. PMID: 26811536.
Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 2014 Dec 4;10(12):e1004861. PMID: 25474007; PMCID: PMC4256268.
HD, AD & PD
Poças GM, Branco-Santos J, Herrera F, Outeiro TF, Domingos PM. α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila. Hum Mol Genet. 2015 Apr 1;24(7):1898-907. PMID: 25452431; PMCID: PMC4355023.
Stroedicke M, Bounab Y, Strempel N, Klockmeier K, Yigit S, Friedrich RP, Chaurasia G, Li S, Hesse F, Riechers SP, Russ J, Nicoletti C, Boeddrich A, Wiglenda T, Haenig C, Schnoegl S, Fournier D, Graham RK, Hayden MR, Sigrist S, Bates GP, Priller J, Andrade-Navarro MA, Futschik ME, Wanker EE. Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity. Genome Res. 2015 May;25(5):701-13. PMID: 25908449; PMCID: PMC4417118.
Spinal Cerebellar Ataxia
Blount JR, Tsou WL, Ristic G, Burr AA, Ouyang M, Galante H, Scaglione KM, Todi SV. Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun. 2014 Aug 21;5:4638. PMID: 25144244; PMCID: PMC4237202.
Prion disease
Steinert JR. Prion protein as a mediator of synaptic transmission. Commun Integr Biol. 2015 Aug 14;8(4):e1063753. PMID: 26478992; PMCID: PMC4594542.
Liu QF, Lee JH, Kim YM, Lee S, Hong YK, Hwang S, Oh Y, Lee K, Yun HS, Lee IS, Jeon S, Chin YW, Koo BS, Cho KS. In Vivo Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using Drosophila Models of Alzheimer's Disease. Biol Pharm Bull. 2015;38(12):1891-901. PMID: 26458335.
Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ. Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease. Sci Rep. 2015 Nov 4;5:16127. PMID: 26530776; PMCID: PMC4632086.
Kong Y, Wu J, Zhang D, Wan C, Yuan L. The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway. Curr Mol Med. 2015;15(10):980-9. PubMed PMID: 26592243.
Peng F, Zhao Y, Huang X, Chen C, Sun L, Zhuang L, Xue L. Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila. Sci Rep. 2015 Nov 24;5:16816. PMID: 26597721; PMCID: PMC4657023.
Geng J, Xia L, Li W, Zhao C, Dou F. Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. J Alzheimers Dis. 2016;49(4):1161-8. PMID: 26599052; PMCID: PMC4927919.
Haddadi M, Nongthomba U, Jahromi SR, Ramesh SR. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration. Behav Brain Res. 2016 Mar 15;301:10-8. PMID: 26706888.
Wang X, Ma Y, Zhao Y, Chen Y, Hu Y, Chen C, Shao Y, Xue L. APLP1 promotes dFoxO-dependent cell death in Drosophila. Apoptosis. 2015 Jun;20(6):778-86. PMID: 25740230.
Lau HC, Lee IK, Ko PW, Lee HW, Huh JS, Cho WJ, Lim JO. Non-invasive screening for Alzheimer's disease by sensing salivary sugar using Drosophila cells expressing gustatory receptor (Gr5a) immobilized on an extended gate ion-sensitive field-effect transistor (EG-ISFET) biosensor. PLoS One. 2015 Feb 25;10(2):e0117810. PMID: 25714733; PMCID: PMC4340960.
Frenkel-Pinter M, Tal S, Scherzer-Attali R, Abu-Hussien M, Alyagor I, Eisenbaum T, Gazit E, Segal D. Naphthoquinone-Tryptophan Hybrid Inhibits Aggregation of the Tau-Derived Peptide PHF6 and Reduces Neurotoxicity. J Alzheimers Dis. 2016;51(1):165-78. PMID: 26836184.
ALS
Chai A, Pennetta G. Insights into ALS pathomechanisms: from flies to humans. Fly (Austin). 2015;9(2):91-8. PMID: 26594942; PMCID: PMC4826116. ---REVIEW
Cragnaz L, Klima R, De Conti L, Romano G, Feiguin F, Buratti E, Baralle M, Baralle FE. An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. Neuroscience. 2015 Dec 17;311:415-21. PMID: 26518462.
Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016 Jan 18;35(2):121-42. PMID: 26702100; PMCID: PMC4718457.
Romano M, Feiguin F, Buratti E. TBPH/TDP-43 modulates translation of Drosophila futsch mRNA through an UG-rich sequence within its 5'UTR. Brain Res. 2016 Sep 15;1647:50-6. doi: 10.1016/j.brainres.2016.02.022. PubMed PMID: 26902497.
FTD/ALS
Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao FB. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron. 2015 Sep 23;87(6):1207-14. PMID: 26402604; PMCID: PMC4589299.
Parkinson's disease
West RJ, Elliott CJ, Wade AR. Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. Sci Rep. 2015 Nov 24;5:16933. PMID: 26597171; PMCID: PMC4657034.
Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015 May 1;24(9):2528-38. PMID: 25612572.
Vos M, Verstreken P, Klein C. Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction. Biochem Soc Trans. 2015 Apr;43(2):275-9. PMID: 25849929.
Wiemerslage L, Lee D. Quantification of mitochondrial morphology in neurites of dopaminergic neurons using multiple parameters. J Neurosci Methods. 2016 Mar 15;262:56-65. PMID: 26777473; PMCID: PMC4775301. ---PROTOCOL
Langston RG, Rudenko IN, Cookson MR. The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research. Biochem J. 2016 Feb 1;473(3):221-32. PMID: 26811536.
Shiba-Fukushima K, Arano T, Matsumoto G, Inoshita T, Yoshida S, Ishihama Y, Ryu KY, Nukina N, Hattori N, Imai Y. Phosphorylation of mitochondrial polyubiquitin by PINK1 promotes Parkin mitochondrial tethering. PLoS Genet. 2014 Dec 4;10(12):e1004861. PMID: 25474007; PMCID: PMC4256268.
HD, AD & PD
Poças GM, Branco-Santos J, Herrera F, Outeiro TF, Domingos PM. α-Synuclein modifies mutant huntingtin aggregation and neurotoxicity in Drosophila. Hum Mol Genet. 2015 Apr 1;24(7):1898-907. PMID: 25452431; PMCID: PMC4355023.
Stroedicke M, Bounab Y, Strempel N, Klockmeier K, Yigit S, Friedrich RP, Chaurasia G, Li S, Hesse F, Riechers SP, Russ J, Nicoletti C, Boeddrich A, Wiglenda T, Haenig C, Schnoegl S, Fournier D, Graham RK, Hayden MR, Sigrist S, Bates GP, Priller J, Andrade-Navarro MA, Futschik ME, Wanker EE. Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity. Genome Res. 2015 May;25(5):701-13. PMID: 25908449; PMCID: PMC4417118.
Spinal Cerebellar Ataxia
Blount JR, Tsou WL, Ristic G, Burr AA, Ouyang M, Galante H, Scaglione KM, Todi SV. Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun. 2014 Aug 21;5:4638. PMID: 25144244; PMCID: PMC4237202.
Prion disease
Steinert JR. Prion protein as a mediator of synaptic transmission. Commun Integr Biol. 2015 Aug 14;8(4):e1063753. PMID: 26478992; PMCID: PMC4594542.
Catching up on Drosophila papers related to neurodegenerative disease--research reports and a review
Alzheimer's disease
Liu QF, Lee JH, Kim YM, Lee S, Hong YK, Hwang S, Oh Y, Lee K, Yun HS, Lee IS, Jeon S, Chin YW, Koo BS, Cho KS. In Vivo Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using Drosophila Models of Alzheimer's Disease. Biol Pharm Bull. 2015;38(12):1891-901. PMID: 26458335.
Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ. Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease. Sci Rep. 2015 Nov 4;5:16127. PMID: 26530776; PMCID: PMC4632086.
Kong Y, Wu J, Zhang D, Wan C, Yuan L. The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway. Curr Mol Med. 2015;15(10):980-9. PubMed PMID: 26592243.
Peng F, Zhao Y, Huang X, Chen C, Sun L, Zhuang L, Xue L. Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila. Sci Rep. 2015 Nov 24;5:16816. PMID: 26597721; PMCID: PMC4657023.
Geng J, Xia L, Li W, Zhao C, Dou F. Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. J Alzheimers Dis. 2016;49(4):1161-8. PMID: 26599052; PMCID: PMC4927919.
Haddadi M, Nongthomba U, Jahromi SR, Ramesh SR. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration. Behav Brain Res. 2016 Mar 15;301:10-8. PMID: 26706888.
Wang X, Ma Y, Zhao Y, Chen Y, Hu Y, Chen C, Shao Y, Xue L. APLP1 promotes dFoxO-dependent cell death in Drosophila. Apoptosis. 2015 Jun;20(6):778-86. PMID: 25740230.
ALS
Chai A, Pennetta G. Insights into ALS pathomechanisms: from flies to humans. Fly (Austin). 2015;9(2):91-8. PMID: 26594942; PMCID: PMC4826116. ---REVIEW
Cragnaz L, Klima R, De Conti L, Romano G, Feiguin F, Buratti E, Baralle M, Baralle FE. An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. Neuroscience. 2015 Dec 17;311:415-21. PMID: 26518462.
Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016 Jan 18;35(2):121-42. PMID: 26702100; PMCID: PMC4718457.
FTD/ALS
Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao FB. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron. 2015 Sep 23;87(6):1207-14. PMID: 26402604; PMCID: PMC4589299.
Parkinson's disease
West RJ, Elliott CJ, Wade AR. Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. Sci Rep. 2015 Nov 24;5:16933. PMID: 26597171; PMCID: PMC4657034.
Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015 May 1;24(9):2528-38. PMID: 25612572.
Vos M, Verstreken P, Klein C. Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction. Biochem Soc Trans. 2015 Apr;43(2):275-9. PMID: 25849929.
Prion disease
Steinert JR. Prion protein as a mediator of synaptic transmission. Commun Integr Biol. 2015 Aug 14;8(4):e1063753. PMID: 26478992; PMCID: PMC4594542.
Liu QF, Lee JH, Kim YM, Lee S, Hong YK, Hwang S, Oh Y, Lee K, Yun HS, Lee IS, Jeon S, Chin YW, Koo BS, Cho KS. In Vivo Screening of Traditional Medicinal Plants for Neuroprotective Activity against Aβ42 Cytotoxicity by Using Drosophila Models of Alzheimer's Disease. Biol Pharm Bull. 2015;38(12):1891-901. PMID: 26458335.
Wang X, Perumalsamy H, Kwon HW, Na YE, Ahn YJ. Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer's disease. Sci Rep. 2015 Nov 4;5:16127. PMID: 26530776; PMCID: PMC4632086.
Kong Y, Wu J, Zhang D, Wan C, Yuan L. The Role of miR-124 in Drosophila Alzheimer's Disease Model by Targeting Delta in Notch Signaling Pathway. Curr Mol Med. 2015;15(10):980-9. PubMed PMID: 26592243.
Peng F, Zhao Y, Huang X, Chen C, Sun L, Zhuang L, Xue L. Loss of Polo ameliorates APP-induced Alzheimer's disease-like symptoms in Drosophila. Sci Rep. 2015 Nov 24;5:16816. PMID: 26597721; PMCID: PMC4657023.
Geng J, Xia L, Li W, Zhao C, Dou F. Cycloheximide Treatment Causes a ZVAD-Sensitive Protease-Dependent Cleavage of Human Tau in Drosophila Cells. J Alzheimers Dis. 2016;49(4):1161-8. PMID: 26599052; PMCID: PMC4927919.
Haddadi M, Nongthomba U, Jahromi SR, Ramesh SR. Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration. Behav Brain Res. 2016 Mar 15;301:10-8. PMID: 26706888.
Wang X, Ma Y, Zhao Y, Chen Y, Hu Y, Chen C, Shao Y, Xue L. APLP1 promotes dFoxO-dependent cell death in Drosophila. Apoptosis. 2015 Jun;20(6):778-86. PMID: 25740230.
ALS
Chai A, Pennetta G. Insights into ALS pathomechanisms: from flies to humans. Fly (Austin). 2015;9(2):91-8. PMID: 26594942; PMCID: PMC4826116. ---REVIEW
Cragnaz L, Klima R, De Conti L, Romano G, Feiguin F, Buratti E, Baralle M, Baralle FE. An age-related reduction of brain TBPH/TDP-43 levels precedes the onset of locomotion defects in a Drosophila ALS model. Neuroscience. 2015 Dec 17;311:415-21. PMID: 26518462.
Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F, Ren H, Chen D, Han J, Ying Z, Wang G. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016 Jan 18;35(2):121-42. PMID: 26702100; PMCID: PMC4718457.
FTD/ALS
Tran H, Almeida S, Moore J, Gendron TF, Chalasani U, Lu Y, Du X, Nickerson JA, Petrucelli L, Weng Z, Gao FB. Differential Toxicity of Nuclear RNA Foci versus Dipeptide Repeat Proteins in a Drosophila Model of C9ORF72 FTD/ALS. Neuron. 2015 Sep 23;87(6):1207-14. PMID: 26402604; PMCID: PMC4589299.
Parkinson's disease
West RJ, Elliott CJ, Wade AR. Classification of Parkinson's Disease Genotypes in Drosophila Using Spatiotemporal Profiling of Vision. Sci Rep. 2015 Nov 24;5:16933. PMID: 26597171; PMCID: PMC4657034.
Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G. The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet. 2015 May 1;24(9):2528-38. PMID: 25612572.
Vos M, Verstreken P, Klein C. Stimulation of electron transport as potential novel therapy in Parkinson's disease with mitochondrial dysfunction. Biochem Soc Trans. 2015 Apr;43(2):275-9. PMID: 25849929.
Prion disease
Steinert JR. Prion protein as a mediator of synaptic transmission. Commun Integr Biol. 2015 Aug 14;8(4):e1063753. PMID: 26478992; PMCID: PMC4594542.
Tuesday, October 6, 2015
Results of two studies suggest disruption of RNA export from nucleus is a mechansim of neurodegenation in ALS and frontodemporal dementia
Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. PMID: 26308899.
From the abstract: "The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. ... To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. ... These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration. "
Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. PMID: 26308891.
From the abstract: "... A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention. "
See also comment in: Fox BW, Tibbetts RS. Neurodegeneration: Problems at the nuclear pore. Nature. 2015 Sep 3;525(7567):36-7. PMID: 26308896.
From the abstract: "The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. ... To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation. We show that these transgenic animals display dosage-dependent, repeat-length-dependent degeneration in neuronal tissues and RAN translation of dipeptide repeat (DPR) proteins, as observed in patients with C9orf72-related disease. This model was used in a large-scale, unbiased genetic screen, ultimately leading to the identification of 18 genetic modifiers that encode components of the nuclear pore complex (NPC), as well as the machinery that coordinates the export of nuclear RNA and the import of nuclear proteins. ... These studies show that a primary consequence of G4C2 repeat expansion is the compromise of nucleocytoplasmic transport through the nuclear pore, revealing a novel mechanism of neurodegeneration. "
Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. PMID: 26308891.
From the abstract: "... A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention. "
See also comment in: Fox BW, Tibbetts RS. Neurodegeneration: Problems at the nuclear pore. Nature. 2015 Sep 3;525(7567):36-7. PMID: 26308896.
Thursday, December 18, 2014
Neurodegenerative models--catching up
Catching up on recent papers related to Drosophila as a model for neurodegenerative diseases.
Fernandes AC, Uytterhoeven V, Kuenen S, Wang YC, Slabbaert JR, Swerts J, Kasprowicz J, Aerts S, Verstreken P. Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration. J Cell Biol. 2014 Nov 24;207(4):453-62. PMID: 25422373; PMCID: PMC4242831. From the abstract: "In this paper, we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, ... Using chimeric fluorescent timers, we show that synaptic vesicle-associated proteins were younger on average ... Using a genetic screen, we find that reducing endosomal-to-lysosomal trafficking ... rescued the neurotransmission and neurodegeneration defects in sky mutants. ... Our findings define a mechanism in which synaptic transmission is facilitated by efficient protein turnover at lysosomes and identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans. "
Vanden Broeck L, Kleinberger G, Chapuis J, Gistelinck M, Amouyel P, Van Broeckhoven C, Lambert JC, Callaerts P, Dermaut B. Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism. Neurobiol Aging. 2014 Sep 28. pii: S0197-4580(14)00596-X. PMID: 25442115.
Jäckel S, Summerer AK, Thömmes CM, Pan X, Voigt A, Schulz JB, Rasse TM, Dormann D, Haass C, Kahle PJ. Nuclear import factor transportin and arginine methyltransferase 1 modify FUS neurotoxicity in Drosophila. Neurobiol Dis. 2014 Nov 8;74C:76-88. PMID: 25447237. From the abstract: "... To investigate the requirements for the nuclear import of FUS in an in vivo model, we generated different transgenic Drosophila lines expressing human FUS wild type (hFUS wt) and two disease-related variants P525L and R495X, in which the NLS is mutated or completely absent, respectively. ..."
Pogson JH, Ivatt RM, Sanchez-Martinez A, Tufi R, Wilson E, Mortiboys H, Whitworth AJ. The Complex I Subunit NDUFA10 Selectively Rescues Drosophila pink1 Mutants through a Mechanism Independent of Mitophagy. PLoS Genet. 2014 Nov 20;10(11):e1004815. doi: 10.1371/journal.pgen.1004815. PMID: 25412178; PMCID: PMC4238976.
Jahromi SR, Haddadi M, Shivanandappa T, Ramesh SR. Modulatory effect of Decalepis hamiltonii on ethanol-induced toxicity in transgenic Drosophila model of Parkinson's disease. Neurochem Int. 2014 Nov 5;80C:1-6. doi: PMID: 25451756.
Siddique YH, Faisal M, Naz F, Jyoti S, Rahul. Role of Ocimum sanctum leaf extract on dietary supplementation in the transgenic Drosophila model of Parkinson's disease. Chin J Nat Med. 2014 Oct;12(10):777-81. PMID: 25443371.
Fernandes AC, Uytterhoeven V, Kuenen S, Wang YC, Slabbaert JR, Swerts J, Kasprowicz J, Aerts S, Verstreken P. Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration. J Cell Biol. 2014 Nov 24;207(4):453-62. PMID: 25422373; PMCID: PMC4242831. From the abstract: "In this paper, we study Drosophila melanogaster lacking active TBC1D24/Skywalker (Sky), a protein that in humans causes severe neurodegeneration, epilepsy, and DOOR (deafness, onychdystrophy, osteodystrophy, and mental retardation) syndrome, ... Using chimeric fluorescent timers, we show that synaptic vesicle-associated proteins were younger on average ... Using a genetic screen, we find that reducing endosomal-to-lysosomal trafficking ... rescued the neurotransmission and neurodegeneration defects in sky mutants. ... Our findings define a mechanism in which synaptic transmission is facilitated by efficient protein turnover at lysosomes and identify a potential strategy to suppress defects arising from TBC1D24 mutations in humans. "
Vanden Broeck L, Kleinberger G, Chapuis J, Gistelinck M, Amouyel P, Van Broeckhoven C, Lambert JC, Callaerts P, Dermaut B. Functional complementation in Drosophila to predict the pathogenicity of TARDBP variants: evidence for a loss-of-function mechanism. Neurobiol Aging. 2014 Sep 28. pii: S0197-4580(14)00596-X. PMID: 25442115.
Jäckel S, Summerer AK, Thömmes CM, Pan X, Voigt A, Schulz JB, Rasse TM, Dormann D, Haass C, Kahle PJ. Nuclear import factor transportin and arginine methyltransferase 1 modify FUS neurotoxicity in Drosophila. Neurobiol Dis. 2014 Nov 8;74C:76-88. PMID: 25447237. From the abstract: "... To investigate the requirements for the nuclear import of FUS in an in vivo model, we generated different transgenic Drosophila lines expressing human FUS wild type (hFUS wt) and two disease-related variants P525L and R495X, in which the NLS is mutated or completely absent, respectively. ..."
Pogson JH, Ivatt RM, Sanchez-Martinez A, Tufi R, Wilson E, Mortiboys H, Whitworth AJ. The Complex I Subunit NDUFA10 Selectively Rescues Drosophila pink1 Mutants through a Mechanism Independent of Mitophagy. PLoS Genet. 2014 Nov 20;10(11):e1004815. doi: 10.1371/journal.pgen.1004815. PMID: 25412178; PMCID: PMC4238976.
Jahromi SR, Haddadi M, Shivanandappa T, Ramesh SR. Modulatory effect of Decalepis hamiltonii on ethanol-induced toxicity in transgenic Drosophila model of Parkinson's disease. Neurochem Int. 2014 Nov 5;80C:1-6. doi: PMID: 25451756.
Siddique YH, Faisal M, Naz F, Jyoti S, Rahul. Role of Ocimum sanctum leaf extract on dietary supplementation in the transgenic Drosophila model of Parkinson's disease. Chin J Nat Med. 2014 Oct;12(10):777-81. PMID: 25443371.
Tuesday, November 11, 2014
Neurodegenerative & neuromuscular disease-related studies--recent reports
Luan Z, Reddig K, Li HS. Loss of Na(+)/K(+)-ATPase in Drosophila photoreceptors leads to blindness and age-dependent neurodegeneration. Exp Neurol. 2014 Nov;261:791-801. doi: 10.1016/j.expneurol.2014.08.025. Epub 2014 PMID: 25205229; PMCID: PMC4194232.
Rosenbaum EE, Vasiljevic E, Cleland SC, Flores C, Colley NJ. The Gos28 SNARE Mediates Intra-Golgi Transport of Rhodopsin and is Required for Photoreceptor Survival. J Biol Chem. 2014 Sep 26. PMID: 25261468.
Barclay SS, Tamura T, Ito H, Fujita K, Tagawa K, Shimamura T, Katsuta A, Shiwaku H, Sone M, Imoto S, Miyano S, Okazawa H. Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1. Hum Mol Genet. 2014 Mar 1;23(5):1345-64. doi: 10.1093/hmg/ddt524. PMID: 24179173. From the abstract: "In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1)."
Xu S, Wilf R, Menon T, Panikker P, Sarthi J, Elefant F. Epigenetic Control of Learning and Memory in Drosophila by Tip60 HAT Action. Genetics. 2014 Oct 17. PMID: 25326235. From the abstract: "Disruption of epigenetic gene control mechanisms in the brain causes significant cognitive impairment that is a debilitating hallmark of most neurodegenerative disorders including Alzheimer's disease (AD). ... Here, we investigate an epigenetic role for the HAT Tip60 in learning and memory formation using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. ... we find that both learning and immediate recall memory deficits that occur under AD associated amyloid precursor protein (APP) induced neurodegenerative conditions can be effectively rescued by increasing Tip60 HAT levels specifically in the MB. ..."
Stepto A, Gallo JM, Shaw CE, Hirth F. Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia. Acta Neuropathol. 2014 Mar;127(3):377-89. PMID: 24366528. From the abstract of this review: "... studies using patient-derived cells, as well as Drosophila and zebrafish models overexpressing disease-related hexanucleotide expansions, can cause repeat length-dependent formation of RNA foci, which directly and progressively correlate with cellular toxicity. ..."
Zwarts L, Van Eijs F, Callaerts P. Glia in Drosophila behavior. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2014 Oct 22. PMID: 25336160. From the abstract: "... We here summarize recent work describing the role of glia in normal behavior and in Drosophila models for neurological and behavioral disorders."
Rosenbaum EE, Vasiljevic E, Cleland SC, Flores C, Colley NJ. The Gos28 SNARE Mediates Intra-Golgi Transport of Rhodopsin and is Required for Photoreceptor Survival. J Biol Chem. 2014 Sep 26. PMID: 25261468.
Barclay SS, Tamura T, Ito H, Fujita K, Tagawa K, Shimamura T, Katsuta A, Shiwaku H, Sone M, Imoto S, Miyano S, Okazawa H. Systems biology analysis of Drosophila in vivo screen data elucidates core networks for DNA damage repair in SCA1. Hum Mol Genet. 2014 Mar 1;23(5):1345-64. doi: 10.1093/hmg/ddt524. PMID: 24179173. From the abstract: "In this study, we performed a systematic in vivo screen of all available Drosophila melanogaster homolog DNA repair genes, and we tested the effect of their overexpression on lifespan and developmental viability in Spinocerebellar Ataxia Type 1 (SCA1) Drosophila models expressing human mutant Ataxin-1 (Atxn1)."
Xu S, Wilf R, Menon T, Panikker P, Sarthi J, Elefant F. Epigenetic Control of Learning and Memory in Drosophila by Tip60 HAT Action. Genetics. 2014 Oct 17. PMID: 25326235. From the abstract: "Disruption of epigenetic gene control mechanisms in the brain causes significant cognitive impairment that is a debilitating hallmark of most neurodegenerative disorders including Alzheimer's disease (AD). ... Here, we investigate an epigenetic role for the HAT Tip60 in learning and memory formation using the Drosophila CNS mushroom body (MB) as a well-characterized cognition model. ... we find that both learning and immediate recall memory deficits that occur under AD associated amyloid precursor protein (APP) induced neurodegenerative conditions can be effectively rescued by increasing Tip60 HAT levels specifically in the MB. ..."
Stepto A, Gallo JM, Shaw CE, Hirth F. Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia. Acta Neuropathol. 2014 Mar;127(3):377-89. PMID: 24366528. From the abstract of this review: "... studies using patient-derived cells, as well as Drosophila and zebrafish models overexpressing disease-related hexanucleotide expansions, can cause repeat length-dependent formation of RNA foci, which directly and progressively correlate with cellular toxicity. ..."
Zwarts L, Van Eijs F, Callaerts P. Glia in Drosophila behavior. J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2014 Oct 22. PMID: 25336160. From the abstract: "... We here summarize recent work describing the role of glia in normal behavior and in Drosophila models for neurological and behavioral disorders."
Tuesday, August 26, 2014
New reports--fly models of neurodegenerative diseases
Catching up on neurodegenerative disease-related reports
Fly study related to ALS
Romano G, Klima R, Buratti E, Verstreken P, Baralle FE, Feiguin F. Chronological requirements of TDP-43 function in synaptic organization and locomotive control. Neurobiol Dis. 2014 Aug 1. pii: S0969-9961(14)00201-0. PMID: 25088713.
Mouse study follows up on potential therapeutic approach to HD identified in Drosophila
Arribat Y, Talmat-Amar Y, Paucard A, Lesport P, Bonneaud N, Bauer C, Bec N, Parmentier ML, Benigno L, Larroque C, Maurel P, Maschat F. Systemic delivery of P42 peptide: a new weapon to fight Huntington's disease. Acta Neuropathol Commun. 2014 Aug 5;2(1):86. PMID: 25091984.
Fly study related to frontotemporal dementia and ALS
Mizielinska S, Grönke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EM, Partridge L, Isaacs AM. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014 Aug 7. pii: 1256800. PMID: 25103406.
BMP signaling & neurodegenerative diseases
Kang MJ, Hansen TJ, Mickiewicz M, Kaczynski TJ, Fye S, Gunawardena S. Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases. PLoS One. 2014 Aug 15;9(8):e104617. PMID: 25127478; PMCID: PMC4134223.
Primary fly larval neuron culture system for study of Alzheimer's disease
Saad Y, Segal D, Ayali A. Enhanced Neurite Outgrowth and Branching Precede Increased Amyloid-β-Induced Neuronal Apoptosis in a Novel Alzheimer's Disease Model. J Alzheimers Dis. 2014 Aug 14. PMID: 25125474
Review and reports related to Parkinson's disease
Chen KF, Crowther DC. Insights into amyloid disease from fly models. Essays Biochem. 2014 Aug 18;56(1):69-83. PMID: 25131587.
Varga SJ, Qi C, Podolsky E, Lee D. A new Drosophila model to study the interaction between genetic and environmental factors in Parkinson׳s disease. Brain Res. 2014 Aug 15. pii: S0006-8993(14)01085-3. PMID: 25130663.
Kimura Y, Fukushi J, Hori S, Matsuda N, Okatsu K, Kakiyama Y, Kawawaki J, Kakizuka A, Tanaka K. Different dynamic movements of wild-type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin-mediated mitochondrial quality control system. Genes Cells. 2013 Dec;18(12):1131-43. PMID: 24215292.
Fly study related to ALS
Romano G, Klima R, Buratti E, Verstreken P, Baralle FE, Feiguin F. Chronological requirements of TDP-43 function in synaptic organization and locomotive control. Neurobiol Dis. 2014 Aug 1. pii: S0969-9961(14)00201-0. PMID: 25088713.
Mouse study follows up on potential therapeutic approach to HD identified in Drosophila
Arribat Y, Talmat-Amar Y, Paucard A, Lesport P, Bonneaud N, Bauer C, Bec N, Parmentier ML, Benigno L, Larroque C, Maurel P, Maschat F. Systemic delivery of P42 peptide: a new weapon to fight Huntington's disease. Acta Neuropathol Commun. 2014 Aug 5;2(1):86. PMID: 25091984.
Fly study related to frontotemporal dementia and ALS
Mizielinska S, Grönke S, Niccoli T, Ridler CE, Clayton EL, Devoy A, Moens T, Norona FE, Woollacott IO, Pietrzyk J, Cleverley K, Nicoll AJ, Pickering-Brown S, Dols J, Cabecinha M, Hendrich O, Fratta P, Fisher EM, Partridge L, Isaacs AM. C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014 Aug 7. pii: 1256800. PMID: 25103406.
BMP signaling & neurodegenerative diseases
Kang MJ, Hansen TJ, Mickiewicz M, Kaczynski TJ, Fye S, Gunawardena S. Disruption of Axonal Transport Perturbs Bone Morphogenetic Protein (BMP) - Signaling and Contributes to Synaptic Abnormalities in Two Neurodegenerative Diseases. PLoS One. 2014 Aug 15;9(8):e104617. PMID: 25127478; PMCID: PMC4134223.
Primary fly larval neuron culture system for study of Alzheimer's disease
Saad Y, Segal D, Ayali A. Enhanced Neurite Outgrowth and Branching Precede Increased Amyloid-β-Induced Neuronal Apoptosis in a Novel Alzheimer's Disease Model. J Alzheimers Dis. 2014 Aug 14. PMID: 25125474
Review and reports related to Parkinson's disease
Chen KF, Crowther DC. Insights into amyloid disease from fly models. Essays Biochem. 2014 Aug 18;56(1):69-83. PMID: 25131587.
Varga SJ, Qi C, Podolsky E, Lee D. A new Drosophila model to study the interaction between genetic and environmental factors in Parkinson׳s disease. Brain Res. 2014 Aug 15. pii: S0006-8993(14)01085-3. PMID: 25130663.
Kimura Y, Fukushi J, Hori S, Matsuda N, Okatsu K, Kakiyama Y, Kawawaki J, Kakizuka A, Tanaka K. Different dynamic movements of wild-type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin-mediated mitochondrial quality control system. Genes Cells. 2013 Dec;18(12):1131-43. PMID: 24215292.
Tuesday, October 29, 2013
Flies & frontotemporal dementia (FTD3). New study implicates Notch signaling. Recent report.
Cheruiyot A, Lee JA, Gao FB, Ahmad ST. Expression of mutant CHMP2B, an ESCRT-III component involved in frontotemporal dementia, causes eye deformities due to Notch misregulation in Drosophila. FASEB J. 2013 Oct 24. PMID: 24158394.
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