Drosophila studies contribute to a study associating variants of PP2A/PPP2R4 with juvenile-onset parkinsonism

Brain. 2022 Sep 8:awac326. doi: 10.1093/brain/awac326 

PTPA variants and impaired PP2A activity in early-onset parkinsonism with
intellectual disability

Fevga C, Tesson C, Mascaro AC, Courtin T, van Coller R, Sakka S, Ferraro F, Farhat N, Bardien S, Damak M, Carr J, Ferrien M, Boumeester V, Hundscheid J, Grillenzoni N, Kessissoglou IA, Kuipers DJS, Quadri M; French and Mediterranean Parkinson disease Genetics Study Group; International Parkinsonism Genetics Network, Corvol JC, Mhiri C, Hassan BA, Breedveld GJ, Lesage S, Mandemakers W, Brice A, Bonifati V

Abstract:

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signaling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau, and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T > G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C > A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA ortholog knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

DOI: 10.1093/brain/awac326
PMID: 36073231

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

Fly model of Tauopathies contributes to study related to pTau interaction with Hsp27

Elife. 2022 Sep 1;11:e79898. doi: 10.7554/eLife.79898.

Specific binding of Hsp27 and phosphorylated Tau mitigates abnormal Tau aggregation-induced pathology.

Zhang S, Zhu Y, Lu J, Liu Z, Lobato AG, Zeng W, Liu J, Qiang J, Zeng S, Zhang Y, Liu C, Liu J, He
Z, Zhai RG, Li D

Abstract:

Amyloid aggregation of phosphorylated Tau (pTau) into neurofibrillary tangles is closely associated with Alzheimer's disease (AD). Several molecular chaperones have been reported to bind Tau and impede its pathological aggregation. Recent findings of elevated levels of Hsp27 in the brains of patients with AD suggested its important role in pTau pathology. However, the molecular mechanism of Hsp27 in pTau aggregation remains poorly understood. Here, we show that Hsp27 partially co-localizes with pTau tangles in the brains of patients with AD. Notably, phosphorylation of Tau by microtubule affinity regulating kinase 2 (MARK2), dramatically enhances the binding affinity of Hsp27 to Tau. Moreover, Hsp27 efficiently prevents pTau fibrillation in vitro and mitigates neuropathology of pTau aggregation in a Drosophila tauopathy model. Further mechanistic study reveals that Hsp27 employs its N-terminal domain to directly interact with multiple phosphorylation sites of pTau for specific binding. Our work provides the structural basis for the specific recognition of Hsp27 to pathogenic pTau, and highlights the important role of Hsp27 in preventing abnormal aggregation and pathology of pTau in AD.

DOI: 10.7554/eLife.79898
PMID: 36048712

Review: "Comprehensive survey" of model organism-based research on rare neurological diseases

Exp Neurobiol. 2022 Feb 28;31(1):1-16. doi: 10.5607/en22003.

Invertebrate Model Organisms as a Platform to Investigate Rare Human Neurological Diseases.

Lee JH

Abstract: 

 Patients suffering from rare human diseases often go through a painful journey for finding a definite molecular diagnosis prerequisite of appropriate cures. With a novel variant isolated from a single patient, determination of its pathogenicity to end such "diagnostic odyssey" requires multi-step processes involving experts in diverse areas of interest, including clinicians, bioinformaticians and research scientists. Recent efforts in building large-scale genomic databases and in silico prediction platforms have facilitated identification of potentially pathogenic variants causative of rare human diseases of a Mendelian basis. However, the functional significance of individual variants remains elusive in many cases, thus requiring incorporation of versatile and rapid model organism (MO)-based platforms for functional analyses. In this review, the current scope of rare disease research is briefly discussed. In addition, an overview of invertebrate MOs for their key features relevant to rare neurological diseases is provided, with the characteristics of two representative invertebrate MOs, Drosophila melanogaster and Caenorhabditis elegans, as well as the challenges against them. Finally, recently developed research networks integrating these MOs in collaborative research are portraited with an array of bioinformatical analyses embedded. A comprehensive survey of MO-based research activities provided in this review will help us to design a well structured analysis of candidate genes or potentially pathogenic variants
for their roles in rare neurological diseases in future.

DOI: 10.5607/en22003
PMID: 35256540

Fly genetic study related to fatal infantile cardioencephalomyopathy, Leigh syndrome, and Charcot-Marie-Tooth disease,

Sci Rep. 2021 Oct 27;11(1):21207. doi: 10.1038/s41598-021-00663-2.

The function of Scox in glial cells is essential for locomotive ability in Drosophila.

Kowada R, Kodani A, Ida H, Yamaguchi M, Lee IS, Okada Y, Yoshida H

Abstract:

Synthesis of cytochrome c oxidase (Scox) is a Drosophila homolog of human SCO2 encoding a metallochaperone that transports copper to cytochrome c, and is an essential protein for the assembly of cytochrome c oxidase in the mitochondrial respiratory chain complex. SCO2 is highly conserved in a wide variety of species across prokaryotes and eukaryotes, and mutations in SCO2 are known to cause mitochondrial diseases such as fatal infantile cardioencephalomyopathy, Leigh syndrome, and Charcot-Marie-Tooth disease, a neurodegenerative disorder. These diseases have a common symptom of locomotive dysfunction. However, the mechanisms of their pathogenesis remain unknown, and no fundamental medications or therapies have been established for these diseases. In this study, we demonstrated that the glial cell-specific knockdown of Scox perturbs the mitochondrial morphology and function, and locomotive behavior in Drosophila. In addition, the morphology and function of synapses were impaired in the glial cell-specific Scox knockdown. Furthermore, Scox knockdown in ensheathing glia, one type of glial cell in Drosophila, resulted in larval and adult locomotive dysfunction. This study suggests that the impairment of Scox in glial cells in the Drosophila CNS mimics the pathological phenotypes observed by mutations in the SCO2 gene in humans.

DOI: 10.1038/s41598-021-00663-2
PMID: 34707123

Reports related to neurodegenerative diseases use Drosophila as a test system

Aging Cell. 2021 Apr 28:e13365. doi: 10.1111/acel.13365. Online ahead of print.

Vesicular glutamate transporter modulates sex differences in dopamine neuron
vulnerability to age-related neurodegeneration.

Buck SA, Steinkellner T, Aslanoglou D, Villeneuve M, Bhatte SH, Childers VC), Rubin SA, De Miranda BR, O'Leary EI, Neureiter EG, Fogle KJ, Palladino MJ, Logan RW, Glausier JR, Fish KN, Lewis DA(2), Greenamyre JT, McCabe BD, Cheetham CEJ, Hnasko TS, Freyberg Z

Age is the greatest risk factor for Parkinson's disease (PD) which causes progressive loss of dopamine (DA) neurons, with males at greater risk than females. Intriguingly, some DA neurons are more resilient to degeneration than others. Increasing evidence suggests that vesicular glutamate transporter (VGLUT) expression in DA neurons plays a role in this selective vulnerability. We investigated the role of DA neuron VGLUT in sex- and age-related differences in DA neuron vulnerability using the genetically tractable Drosophila model. We found sex differences in age-related DA neurodegeneration and its associated locomotor behavior, where males exhibit significantly greater decreases in both DA neuron number and locomotion during aging compared with females. We discovered that dynamic changes in DA neuron VGLUT expression mediate these age- and sex-related differences, as a potential compensatory mechanism for diminished DA neurotransmission during aging. Importantly, female Drosophila possess higher levels of VGLUT expression in DA neurons compared with males, and this finding is conserved across flies, rodents, and humans. Moreover, we showed that diminishing VGLUT expression in DA neurons eliminates females' greater resilience to DA neuron loss across aging. This offers a new mechanism for sex differences in selective DA neuron vulnerability to age-related DA neurodegeneration. Finally, in mice, we showed that the ability of DA neurons to achieve optimal control over VGLUT expression is essential for DA neuron survival. These findings lay the groundwork for the manipulation of DA neuron VGLUT expression as a novel therapeutic strategy to boost DA neuron resilience to age- and PD-related neurodegeneration.

DOI: 10.1111/acel.13365
PMID: 33909313

 

Cell Death Dis. 2020 Sep 10;11(9):739. doi: 10.1038/s41419-020-02942-8.

Enhanced accumulation of reduced glutathione by Scopoletin improves
survivability of dopaminergic neurons in Parkinson's model.

Pradhan P, Majhi O, Biswas A, Joshi VK, Sinha D

Parkinson's disease (PD) is a neuromotor disorder, primarily manifested by motor anomalies due to progressive loss of dopaminergic neurons. Although alterations in genetic factors have been linked with its etiology, exponential accumulation of environmental entities such as reactive oxygen species (ROS) initiate a cyclic chain reaction resulting in accumulation of cellular inclusions, dysfunctional mitochondria, and overwhelming of antioxidant machinery, thus accelerating disease pathogenesis. Involvement of oxidative stress in PD is further substantiated through ROS induced Parkinsonian models and elevated oxidative markers in clinical PD samples; thereby, making modulation of neuronal oxidative load as one of the major approaches in management of PD. Here we have found a potent antioxidant moiety Scopoletin (Sp), a common derivative in most of the nootropic herbs, with robust neuroprotective ability. Sp increased cellular resistance to ROS through efficient recycling of GSH to prevent oxidative damage. The Sp treated cells showed higher loads of reduced glutathione making them resistant to perturbation of antioxidant machinery or neurotoxin MPP+. Sp could restore the redox balance, mitochondrial function, and prevented oxidative damage, leading to recovery of dopaminergic neural networks and motion abilities in Drosophila genetic model of PD. Our data also suggest that Sp, in combination increases the therapeutic potency of L-DOPA by mitigating its chronic toxicity. Together, we highlight the possible ability of Sp in preventing oxidative stress mediated loss of dopaminergic neurons and at the same time enhance the efficacy of dopamine recharging regimens.

DOI: 10.1038/s41419-020-02942-8
PMCID: PMC7484898
PMID: 32913179

Cross-species analysis related to Huntington's disease (fly, mouse, human)

Elife. 2021 Apr 19;10:e64564. doi: 10.7554/eLife.64564. Online ahead of print.

Downregulation of glial genes involved in synaptic function mitigates Huntington's Disease pathogenesis.

Onur TS, Laitman A, Zhao H, Keyho R, Kim H, Wang J, Mair M, Wang H, Li L, Perez A, de Haro M, Wan YW, Allen G, Lu B, Al-Ramahi I, Liu Z, Botas J

Abstract:

Most research on neurodegenerative diseases has focused on neurons, yet glia help form and maintain the synapses whose loss is so prominent in these conditions. To investigate the contributions of glia to Huntington's disease (HD), we profiled the gene expression alterations of Drosophila expressing human mutant Huntingtin (mHTT) in either glia or neurons and compared these changes to what is observed in HD human and HD mice striata. A large portion of conserved genes are concordantly dysregulated across the three species; we tested these genes in a high-throughput behavioral assay and found that downregulation of genes involved in synapse assembly mitigated pathogenesis and behavioral deficits. To our surprise, reducing dNRXN3 function in glia was sufficient to improve the phenotype of flies expressing mHTT in neurons, suggesting that mHTT's toxic effects in glia ramify throughout the brain. This supports a model in which dampening synaptic function is protective because it attenuates the  excitotoxicity that characterizes HD.

DOI: 10.7554/eLife.64564
PMID: 33871358

Light-activated receptors tested in Drosophila model of Parkinson's disease

PLoS Genet. 2021 Apr 15;17(4):e1009479. doi: 10.1371/journal.pgen.1009479.

Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease.

Ingles-Prieto A, Furthmann N, Crossman SH Tichy AM, Hoyer N, Petersen M, Zheden V, Biebl J, Reichhart E, Gyoergy A, Siekhaus DE, Soba P, Winklhofer KF, Janovjak H

Abstract:

Optogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson's disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to inspire novel strategies towards a spatio-temporal regulation of tissue repair.

DOI: 10.1371/journal.pgen.1009479
PMID: 33857132

Drosophila models of oculopharyngeal muscular dystrophy (OPMD) included in study seeking therapeutic strategies for treating prion diseases

Neurotherapeutics. 2021 Feb 2. doi: 10.1007/s13311-020-00992-6

Anti-prion Drugs Targeting the Protein Folding Activity of the Ribosome Reduce PABPN1 Aggregation

Bamia A, Sinane M, Naït-Saïdi R, Dhiab J, Keruzoré M, Nguyen PH, Bertho A, Soubigou F, Halliez S, Blondel M, Trollet C, Simonelig M, Friocourt G, Béringue V, Bihel F, Voisset C

From the abstract: Prion diseases are caused by the propagation of PrPSc, the pathological conformation of the PrPC prion protein ... and no therapeutic solution is currently available. We thus sought to identify new anti-prion molecules and found that flunarizine inhibited PrPSc propagation in cell culture and significantly prolonged survival of prion-infected mice. Using an in silico therapeutic repositioning approach based on similarities with flunarizine chemical structure, we tested azelastine, duloxetine, ebastine, loperamide and metixene and showed that they all have an anti-prion activity. ... Strikingly, some of these drugs were also able to alleviate phenotypes due to PABPN1 nuclear aggregation in cell and Drosophila models of oculopharyngeal muscular dystrophy (OPMD). These data emphasize the therapeutic potential of anti-PFAR drugs for neurodegenerative and neuromuscular proteinopathies.

DOI: 10.1007/s13311-020-00992-6
PMID: 33533011

Fly model leads to new model for cellular mechanisms underlying diseases associated with disruption of Valosin-Containing Proteins

Nat Commun. 2021 Jan 21;12(1):513. doi: 10.1038/s41467-020-20796-8.

SVIP is a molecular determinant of lysosomal dynamic stability, neurodegeneration and lifespan.

Johnson AE, Orr BO, Fetter RD, Moughamian AJ, Primeaux LA,
Geier EG, Yokoyama JS, Miller BL, Davis GW
 

From the abstract:

Missense mutations in Valosin-Containing Protein (VCP) are linked to diverse degenerative diseases including IBMPFD, amyotrophic lateral sclerosis (ALS), muscular dystrophy and Parkinson's disease. Here, we characterize a VCP-binding co-factor (SVIP) that specifically recruits VCP to lysosomes. ... We also establish multiple links between SVIP and VCP-dependent disease in our Drosophila model system. ... Finally, we identify a human SVIP mutation and confirm the pathogenicity of this mutation in our Drosophila model. We propose a model for VCP disease based on the differential, co-factor-dependent recruitment of VCP to intracellular organelles.

DOI: 10.1038/s41467-020-20796-8
PMID: 33479240

Wondering what's IBMPFD? Answer: Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia.

Fly model of Menkes and Wilson's diseases used to explore cellular mechanisms

Hartwig C, Méndez GM, Bhattacharjee S, Vrailas-Mortimer AD, Zlatic SA, Freeman AAH, Gokhale A, Concilli M, Werner E, Sapp Savas C, Rudin-Rush S, Palmer L, Shearing N, Margewich L, McArthy J, Taylor S, Roberts B, Lupashin V, Polishchuk RS, Cox DN, Jorquera RA, Faundez V. Golgi-Dependent Copper Homeostasis Sustains Synaptic Development and Mitochondrial Content. J Neurosci. 2020 Nov 17:JN-RM-1284-20. doi: 10.1523/JNEUROSCI.1284-20.2020. PMID: 33208468.

From the abstract:

Rare genetic diseases preponderantly affect the nervous system causing neurodegeneration to neurodevelopmental disorders. This is the case for both Menkes and Wilson disease, arising from mutations in ATP7A and ATP7B, respectively. The ATP7A and ATP7B proteins localize to the Golgi and regulate copper homeostasis. We demonstrate genetic and biochemical interactions between ATP7 paralogs with the Conserved Oligomeric Golgi complex, or COG complex, a Golgi apparatus vesicular tether. Disruption of Drosophila copper homeostasis by ATP7 tissue-specific transgenic expression caused alterations in epidermis, aminergic, sensory, and motor neurons. ... We conclude that the integrity of Golgi-dependent copper homeostasis mechanisms, requiring ATP7 and COG, are necessary to maintain mitochondria functional integrity and localization to synapses. ... These findings suggest communication between the Golgi apparatus and mitochondria through homeostatically controlled cellular copper levels and copper-dependent enzymatic activities in both organelles.

Drosophila as a "3Rs" (Replace, Reduce and Refine) model system is emphasized in a study with potential relevance to neurodegenerative disease

Gonçalves-Pimentel C, Mazaud D, Kottler B, Proelss S, Hirth F, Fanto M. A miRNA screen procedure identifies garz as an essential factor in adult glia functions and validates Drosophila as a beneficial 3Rs model to study glial functions and GBF1 biology. F1000Res. 2020 May 1;9:317. doi:
10.12688/f1000research.23154.2. PMID: 32595956; PMCID: PMC7309417.

 

Abstract:

"Invertebrate glia performs most of the key functions controlled by mammalian glia in the nervous system and provides an ideal model for genetic studies of glial functions. To study the influence of adult glial cells in ageing we have performed a genetic screen in Drosophila using a collection of transgenic lines providing conditional expression of micro-RNAs (miRNAs). Here, we describe a methodological algorithm to identify and rank genes that are candidate to be targeted by miRNAs that shorten lifespan when expressed in adult glia. We have used four different databases for miRNA target prediction in Drosophila but find little agreement between them, overall. However, top candidate gene analysis shows potential to identify essential genes involved in adult glial functions. One example from our top candidates' analysis is gartenzwerg ( garz). We establish that garz is necessary in many glial cell types, that it affects motor behaviour and, at the sub-cellular level, is responsible for defects in cellular membranes, autophagy and mitochondria quality control. We also verify the remarkable conservation of functions between garz and its mammalian orthologue, GBF1, validating the use of Drosophila as an alternative 3Rs-beneficial model to knock-out mice for studying the biology of GBF1, potentially involved in human neurodegenerative diseases."

Results using a fly model of Parkinsons Disease suggests Skp1 is a potential therapeutic target for neurodegenerative diseases

iScience. 2020 Jul 16;23(8):101375. doi: 10.1016/j.isci.2020.101375. Online
ahead of print.

Drosophila Skp1 Homologue SkpA Plays a Neuroprotective Role in Adult Brain.

Dabool L, Hakim-Mishnaevski K, Juravlev L, Flint-Brodsly N, Mandel

S, Kurant E.

Abstract:

Skp1, a component of the ubiquitin E3 ligases, was found to be decreased in the brains of sporadic Parkinson's disease (PD) patients, and its overexpression prevented death of murine neurons in culture. Here we expose the neuroprotective role of the Drosophila skp1 homolog, skpA, in the adult brain. Neuronal knockdown of skpA leads to accumulation of ubiquitinated protein aggregates and loss of dopaminergic neurons accompanied by motor dysfunction and reduced lifespan. Conversely, neuronal overexpression of skpA reduces aggregate load, improves age-related motor decline, and prolongs lifespan. Moreover, SkpA rescues neurodegeneration in a Drosophila model of PD. We also show that a Drosophila homolog of FBXO7, the F Box protein, Nutcracker (Ntc), works in the same pathway with SkpA. However, skpA overexpression rescues ntc knockdown phenotype, suggesting that SkpA interacts with additional F box proteins in the adult brain neurons. Collectively, our study discloses Skp1/SkpA as a potential therapeutic target in neurodegenerative diseases.

DOI: 10.1016/j.isci.2020.101375
PMID: 32739834

New fly models of Spinocerebellar ataxia type 31

Ishikawa K, Nagai Y. Molecular Mechanisms and Future Therapeutics for Spinocerebellar Ataxia Type 31 (SCA31). Neurotherapeutics. 2019 Nov 21. PubMed PMID: 31755042.

From the abstract: "Spinocerebellar ataxia type 31 (SCA31) is one of the autosomal-dominant neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom. This disease is caused by a 2.5- to 3.8-kb-long complex pentanucleotide repeat containing (TGGAA)n, (TAGAA)n, (TAAAA)n, and (TAAAATAGAA)n in an intron of the gene called BEAN1 (brain expressed, associated with Nedd4). ... To dissect the pathogenesis of (UGGAA)n in SCA31, we generated transgenic fly models of SCA31 by overexpressing SCA31 complex pentanucleotide repeats in Drosophila. We found that the toxicity of (UGGAA)n is length- and expression level-dependent, and it was dampened by co-expressing TDP-43, FUS, and hnRNP A2/B1. ..."

Studies in Drosophila point to potential therapeutic approach for treatment of Parkinson's Disease based on modulation of kynurenine metabolism

Cunningham PC, Waldeck K, Ganetzky B, Babcock DT. Neurodegeneration and locomotor dysfunction in Drosophila scarlet mutants. J Cell Sci. 2018 Sep 17;131(18). pii: jcs216697. doi: 10.1242/jcs.216697. PubMed PMID: 30154211; PubMed Central PMCID: PMC6176922.

From the abstract: "Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons, resulting in progressive locomotor dysfunction. Identification of genes required for the maintenance of these neurons should help to identify potential therapeutic targets. ... Here, we show that Drosophila melanogaster scarlet mutants exhibit an age-dependent progressive loss of dopaminergic neurons, along with subsequent locomotor defects and a shortened lifespan. ... we show that expression of wild-type Scarlet is neuroprotective in a model of PD, suggesting that manipulating kynurenine metabolism may be a potential therapeutic option in treating PD."

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."

Drosophila model of amyloid-beta aggregation used in study that helps inform mechanistic understanding related to Alzheimer's disease

Stapper ZA, Jahn TR. Changes in Glutathione Redox Potential Are Linked to Aβ(42)-Induced Neurotoxicity. Cell Rep. 2018 Aug 14;24(7):1696-1703. PMID: 30110626.

Abstract: "Glutathione is the major low-molecular weight thiol of eukaryotic cells. It is central to one of the two major NADPH-dependent reducing systems and is likely to play a role in combating oxidative stress, a process suggested to play a key role in Alzheimer's disease (AD). However, the nature and relevance of redox changes in the onset and progression of AD are still uncertain. Here, we combine genetically encoded redox sensors with our Drosophila models of amyloid-beta (Aβ) aggregation. We find that changes in glutathione redox potential (EGSH) closely correlate with disease onset and progression. We observe this redox imbalance specifically in neurons, but not in glia cells. EGSH changes and Aβ42 deposition are also accompanied by increased JNK stress signaling. Furthermore, pharmacologic and genetic manipulation of glutathione synthesis modulates Aβ42-mediated neurotoxicity, suggesting a causal relationship between disturbed glutathione redox homeostasis and early AD pathology."

Drosophila model used to explore mechanisms related to Alzheimer's disease

Zhuang L, Peng F, Huang Y, Li W, Huang J, Chu Y, Ren P, Sun Y, Zhang Y, Xue E, Guo X, Shen X, Xue L. CHIP modulates APP-induced autophagy-dependent pathological symptoms in Drosophila. Aging Cell. 2019 Nov 28:e13070. PubMed PMID: 31777182.

Abstract: "Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether autophagy is a cause or consequence of AD. We have previously expressed the full-length human APP in Drosophila and established a fly AD model that exhibits multiple AD-like symptoms. Here we report that depletion of CHIP effectively palliated APP-induced pathological symptoms, including morphological, behavioral, and cognitive defects. Mechanistically, CHIP is required for APP-induced autophagy dysfunction, which promotes Aβ production via increased expression of BACE and Psn. Our findings suggest that aberrant autophagy is not only a consequence of abnormal APP activity, but also contributes to dysregulated APP metabolism and subsequent AD pathogenesis."

Review: "Insights from Drosophila melanogaster model of Alzheimer's disease"

Tue NT, Dat TQ, Ly LL, Anh VD, Yoshida H. Insights from Drosophila melanogaster model of Alzheimer's disease. Front Biosci (Landmark Ed). 2020 Jan 1;25:134-146. PubMed PMID: 31585881.

Abstract: "Alzheimer's disease (AD) is a common chronic neurodegenerative disease that mainly affects the medial temporal lobe and associated neocortical structures. The disease process involves two abnormal structures, plaques and tangles, which damage and destroy nerve cells. Tangles are twisted fibers of tau protein that build up inside cells. Plaques are deposits of a protein fragment called amyloid-beta (Aβ) that accumulate in the spaces between nerve cells. Aβ derives from the amyloid precursor protein and is the main component of amyloid plaques in the AD brain. Although AD has been extensively examined, its pathogenetic mechanisms remain unclear and there are currently no effective drugs for this disorder. Many AD model systems have recently been established using Drosophila melanogaster by expressing the proteins involved in AD in the brain. These systems successfully reflect some of the symptoms associated with AD such as the onset of learning defects, age-dependent short-term memory impairment, increase of wakefulness and consolidated sleep disruption by expressing human Aβ42 or human APP/BACE in Drosophila central nervous system. We herein discuss these Drosophila AD models."

'Multilayered' approach to study of Huntington Disease includes testing in fly HD models

Al-Ramahi I, Lu B, Di Paola S, Pang K, de Haro M, Peluso I, Gallego-Flores T, Malik NT, Erikson K, Bleiberg BA, Avalos M, Fan G, Rivers LE, Laitman AM, Diaz-García JR, Hild M, Palacino J, Liu Z, Medina DL, Botas J. High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration. Cell Syst. 2018 Jul 25;7(1):28-40.e4. PubMed PMID: 29936182; PubMed Central PMCID: PMC6082401.

Abstract: "Discriminating transcriptional changes that drive disease pathogenesis from nonpathogenic and compensatory responses is a daunting challenge. This is particularly true for neurodegenerative diseases, which affect the expression of thousands of genes in different brain regions at different disease stages. Here we integrate functional testing and network approaches to analyze previously reported transcriptional alterations in the brains of Huntington disease (HD) patients. We selected 312 genes whose expression is dysregulated both in HD patients and in HD mice and then replicated and/or antagonized each alteration in a Drosophila HD model. High-throughput behavioral testing in this model and controls revealed that transcriptional changes in synaptic biology and calcium signaling are compensatory, whereas alterations involving the actin cytoskeleton and inflammation drive disease. Knockdown of disease-driving genes in HD patient-derived cells lowered mutant Huntingtin levels and activated macroautophagy, suggesting a mechanism for mitigating pathogenesis. Our multilayered approach can thus untangle the wealth of information generated by transcriptomics and identify early therapeutic intervention points."