Assay in fly eye contributes to study related to ALS & FTD

J Biol Chem. 2022 Aug;298(8):102191. doi: 10.1016/j.jbc.2022.102191. 

Casein kinase 1δ/ε phosphorylates fused in sarcoma (FUS) and ameliorates FUS-mediated neurodegeneration

Kishino Y, Matsukawa K, Matsumoto T, Miyazaki R, Wakabayashi T, Nonaka T, Kametani F, Hasegawa M, Hashimoto T, Iwatsubo T

From the abstract:

Aberrant cytoplasmic accumulation of an RNA-binding protein, fused in sarcoma (FUS), characterizes the neuropathology of subtypes of ALS and frontotemporal lobar degeneration ... we show that casein kinase 1δ (CK1δ) phosphorylates FUS at 10 serine/threonine residues in vitro ... We also show that phosphorylation by CK1δ or CK1ε significantly increased the solubility of FUS in human embryonic kidney 293 cells. In transgenic Drosophila that overexpress wt or P525L ALS-mutant human FUS in the retina or in neurons, we found coexpression of human CK1δ or its Drosophila isologue Dco in the photoreceptor neurons significantly ameliorated the observed retinal degeneration, and neuronal coexpression of human CK1δ extended fly life span. .. our data suggest a novel regulatory mechanism of the assembly and toxicity of FUS through CK1δ/CK1ε-mediated phosphorylation, which could represent a potential therapeutic target in FUS proteinopathies.

DOI: 10.1016/j.jbc.2022.102191
PMCID: PMC9293781
PMID: 35753345

PubMedCentral: Fly model used in studies related to ALS and FTLD

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."

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."

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.

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."

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 ..."

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."

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."

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.

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.

Drosophila model used to explore mechanisms underlying microsatellite expansion-induced neurodegeneration

Schweizer Burguete A, Almeida S, Gao FB, Kalb R, Akins MR, Bonini NM. GGGGCC microsatellite RNA is neuritically localized, induces branching defects, and perturbs transport granule function. Elife. 2015 Dec 9;4. PMID: 26650351.

From the abstract: "Microsatellite expansions are the leading cause of numerous neurodegenerative disorders. Here we demonstrate that GGGGCC and CAG microsatellite repeat RNAs associated with C9orf72 in ALS/FTD and with polyglutamine diseases, respectively, localize to neuritic granules that undergo active transport into distal neuritic segments. ... Using a Drosophila GGGGCC expansion disease model, we characterize dendritic branching defects that are modulated by FMRP and Orb2. ... These data suggest that expanded repeat RNAs interact with the mRNA transport and translation machinery, causing transport granule dysfunction. This could be a novel mechanism contributing to the neuronal defects associated with C9orf72 and other microsatellite expansion diseases."

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.

New fly model: VCP mutation-dependent degeneration. Recent report.

Kim NC, Tresse E, Kolaitis RM, Molliex A, Thomas RE, Alami NH, Wang B, Joshi A, Smith RB, Ritson GP, Winborn BJ, Moore J, Lee JY, Yao TP, Pallanck L, Kundu M, Taylor JP. VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron. 2013 Apr 10;78(1):65-80. PMID: 23498974.

From the abstract: "Mutations in VCP cause multisystem degeneration impacting the nervous system, muscle, and/or bone. Patients may present with ALS, Parkinsonism, frontotemporal dementia, myopathy, Paget's disease, or a combination of these. The disease mechanism is unknown. We developed a Drosophila model of VCP mutation-dependent degeneration."

A related paper using human cells appears in the same issue of the journal. Bartolome et al. Pathogenic VCP mutations induce mitochondrial uncoupling and reduced ATP levels. Neuron. 2013 Apr 10;78(1):57-64. PMID: 23498975.

Fly models of ALS and frontotemporal lobar degeneration. Links to glutamate transport. Recent report.

Diaper DC, Adachi Y, Lazarou L, Greenstein M, Simoes FA, Di Domenico A, Solomon DA, Lowe S, Alsubaie R, Cheng D, Buckley S, Humphrey DM, Shaw CE, Hirth F. Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioral phenotypes that characterize ALS and FTLD. Hum Mol Genet. 2013 May 31. PMID: 23727833.

Loss versus gain of TDP-43 study. Recent report.

Diaper DC, Adachi Y, Sutcliffe B, Humphrey DM, Elliott CJ, Stepto A, Ludlow ZN, Broeck LV, Callaerts P, Dermaut B, Al-Chalabi A, Shaw CE, Robinson IM, Hirth F. Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes. Hum Mol Genet. 2013 Jan 10. PMID: 23307927.