Biology subjects

Feany, M. B.

Publications and source records attributed to Feany, M. B..

10 recordsLinked to original sources

bioRxiv2026

Single cell eQTL mapping reveals convergent glial-neuronal risk architecture in Parkinson's disease

Synucleinopathies affect [~]15 million people and are classically divided into neuronal (Parkinsons disease (PD), dementia with Lewy bodies) and glial (multiple system atrophy) disorders. Here we challenge this dichotomy. We functionally fine-map 90 PD GWAS signals across nine cell types in cortex and substantia nigra using disease-context, population-scale single-nucleus eQTL meta-analysis (N = 1,197), bulk brain eQTL analysis (N = 1,182), and Mendelian randomization. A stringent causal framework integrates single-nucleus allelic imbalance (snASE) with orthogonal validation. We identify 125 functional risk genes for 50 loci--nearly doubling supported genes--and assign genes and cell types to over half of GWAS signals. Unexpectedly, 51% of risk genes are regulated in glia, particularly oligodendrocytes and their precursors. Across cell types, risk converges on a shared glial-neuronal vesiculopathy network. These findings uncover a convergent glial-neuronal risk architecture and establish a single-cell atlas for context-aware gene discovery and precision therapeutics for PD.

genetics↗

bioRxiv2024

A systems-biology approach connects aging mechanisms with Alzheimer's disease pathogenesis

Despite years of intense investigation, the mechanisms underlying neuronal death in Alzheimers disease, the most common neurodegenerative disorder, remain incompletely understood. To define relevant pathways, we integrated the results of an unbiased, genome-scale forward genetic screen for age-associated neurodegeneration in Drosophila with human and Drosophila Alzheimers disease-associated multi-omics. We measured proteomics, phosphoproteomics, and metabolomics in Drosophila models of Alzheimers disease and identified Alzheimers disease human genetic variants that modify expression in disease-vulnerable neurons. We used a network optimization approach to integrate these data with previously published Alzheimers disease multi-omic data. We computationally predicted and experimentally demonstrated how HNRNPA2B1 and MEPCE enhance tau-mediated neurotoxicity. Furthermore, we demonstrated that the screen hits CSNK2A1 and NOTCH1 regulate DNA damage in Drosophila and human iPSC-derived neural progenitor cells. Our work identifies candidate pathways that could be targeted to ameliorate neurodegeneration in Alzheimers disease.

systems biology↗

bioRxiv2024

Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies

Whether neurodegenerative diseases linked to misfolding of the same protein share genetic risk drivers or whether different protein-aggregation pathologies in neurodegeneration are mechanistically related remains uncertain. Conventional genetic analyses are underpowered to address these questions. Through careful selection of patients based on protein aggregation phenotype (rather than clinical diagnosis) we can increase statistical power to detect associated variants in a targeted set of genes that modify proteotoxicities. Genetic modifiers of alpha-synuclein ([a]S) and beta-amyloid (A{beta}) cytotoxicity in yeast are enriched in risk factors for Parkinsons disease (PD) and Alzheimers disease (AD), respectively. Here, along with known AD/PD risk genes, we deeply sequenced exomes of 430 [a]S/A{beta} modifier genes in patients across alpha-synucleinopathies (PD, Lewy body dementia and multiple system atrophy). Beyond known PD genes GBA1 and LRRK2, rare variants AD genes (CD33, CR1 and PSEN2) and A{beta} toxicity modifiers involved in RhoA/actin cytoskeleton regulation (ARGHEF1, ARHGEF28, MICAL3, PASK, PKN2, PSEN2) were shared risk factors across synucleinopathies. Actin pathology occurred in iPSC synucleinopathy models and RhoA downregulation exacerbated [a]S pathology. Even in sporadic PD, the expression of these genes was altered across CNS cell types. Genome-wide CRISPR screens revealed the essentiality of PSEN2 in both human cortical and dopaminergic neurons, and PSEN2 mutation carriers exhibited diffuse brainstem and cortical synucleinopathy independent of AD pathology. PSEN2 contributes to a common-risk signal in PD GWAS and regulates [a]S expression in neurons. Our results identify convergent mechanisms across synucleinopathies, some shared with AD.

genomics↗

bioRxiv2024

Pathways controlling neurotoxicity and proteostasis in mitochondrial complex I deficiency

Neuromuscular disorders caused by dysfunction of the mitochondrial respiratory chain are common, severe and untreatable. We recovered a number of mitochondrial genes, including electron transport chain components, in a large forward genetic screen for mutations causing age-related neurodegeneration in the context of proteostasis dysfunction. We created a model of complex I deficiency in the Drosophila retina to probe the role of protein degradation abnormalities in mitochondrial encephalomyopathies. Using our genetic model, we found that complex I deficiency regulates both the ubiquitin/proteasome and autophagy/lysosome arms of the proteostasis machinery. We further performed an in vivo kinome screen to uncover new and potentially druggable mechanisms contributing to complex I related neurodegeneration and proteostasis failure. Reduction of RIOK kinases and the innate immune signaling kinase pelle prevented neurodegeneration in complex I deficiency animals. Genetically targeting oxidative stress, but not RIOK1 or pelle knockdown, normalized proteostasis markers. Our findings outline distinct pathways controlling neurodegeneration and protein degradation in complex I deficiency and introduce an experimentally facile model in which to study these debilitating and currently treatment-refractory disorders.

neuroscience↗

bioRxiv2023

Integrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging

A{beta} peptides derived from the amyloid precursor protein (APP) have been strongly implicated in the pathogenesis of Alzheimers disease. However, the normal function of APP and the importance of that role in neurodegenerative disease is less clear. We recovered the Drosophila ortholog of APP, Appl, in an unbiased forward genetic screen for neurodegeneration mutants. We performed comprehensive single cell transcriptional and proteomic studies of Appl mutant flies to investigate Appl function in the aging brain. We found an unexpected role for Appl in control of multiple cellular pathways, including translation, mitochondrial function, nucleic acid and lipid metabolism, cellular signaling and proteostasis. We mechanistically defined a role for Appl in regulating autophagy through TGF{beta} signaling and documented the broader relevance of our findings using mouse genetic, human iPSC and in vivo tauopathy models. Our results demonstrate a conserved role for APP in controlling age-dependent proteostasis with plausible relevance to Alzheimers disease.

neuroscience↗

bioRxiv2023

A Drosophila model of chemotherapy-related cognitive impairment

Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model of CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurocognitive deficits were observed with all tested chemotherapies, especially cisplatin. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model of CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI and pharmacologic screens to identify novel therapies to ameliorate CRCI. Summary StatementWe present a Drosophila model of chemotherapy-related cognitive impairment, which recapitulates neurocognitive and neuropathologic changes observed in cancer patients treated with chemotherapy.

animal behavior and cognition↗

bioRxiv2023

α-synuclein promotes neuronal dysfunction and death by disrupting the binding of ankyrin to β-spectrin

-synuclein plays a key role in the pathogenesis of Parkinsons disease and related disorders, but critical interacting partners and molecular mechanisms mediating neurotoxicity are incompletely understood. We show that -synuclein binds directly to {beta}-spectrin. Using males and females in a Drosophila model of -synuclein-related disorders we demonstrate that {beta}-spectrin is critical for -synuclein neurotoxicity. Further, the ankyrin binding domain of {beta}-spectrin is required for -synuclein binding and neurotoxicity. A key plasma membrane target of ankyrin, Na+/K+ ATPase, is mislocalized when human -synuclein is expressed in Drosophila. Accordingly, membrane potential is depolarized in -synuclein transgenic fly brains. We examine the same pathway in human neurons and find that Parkinsons disease patient-derived neurons with a triplication of the -synuclein locus show disruption of the spectrin cytoskeleton, mislocalization of ankyrin and Na+/K+ ATPase, and membrane potential depolarization. Our findings define a specific molecular mechanism by which elevated levels of -synuclein in Parkinsons disease and related -synucleinopathies leads to neuronal dysfunction and death. Significance StatementThe small synaptic vesicle associate protein -synuclein plays a critical role in the pathogenesis of Parkinsons disease and related disorders, but the disease-relevant binding partners of -synuclein and proximate pathways critical for neurotoxicity require further definition. We show that -synuclein binds directly to {beta}-spectrin, a key cytoskeletal protein required for localization of plasma membrane proteins and maintenance of neuronal viability. Binding of -synuclein to {beta}-spectrin alters the organization of the spectrin-ankyrin complex, which is critical for localization and function of integral membrane proteins, including Na+/K+ ATPase. These finding outline a previously undescribed mechanism of -synuclein neurotoxicity and thus suggest potential new therapeutic approaches in Parkinsons disease and related disorders.

neuroscience↗

bioRxiv2023

Circular RNAs in the human brain are tailored to neuron identity and neuropsychiatric disease

Little is known about circular RNAs (circRNAs) in specific brain cells and human neuropsychiatric disease. Here, we systematically identified over 11,039 circRNAs expressed in vulnerable dopamine and pyramidal neurons laser-captured from 190 human brains and non-neuronal cells using ultra-deep, total RNA sequencing. 1,526 and 3,308 circRNAs were custom-tailored to the cell identity of dopamine and pyramidal neurons and enriched in synapse pathways. 88% of Parkinsons and 80% of Alzheimers disease-associated genes produced circRNAs. circDNAJC6, produced from a juvenile-onset Parkinsons gene, was already dysregulated during prodromal, onset stages of common Parkinsons disease neuropathology. Globally, addiction-associated genes preferentially produced circRNAs in dopamine neurons, autism-associated genes in pyramidal neurons, and cancers in non-neuronal cells. This study shows that circular RNAs in the human brain are tailored to neuron identity and implicate circRNA- regulated synaptic specialization in neuropsychiatric diseases.

genomics↗

bioRxiv2022

Nicotine-mediated rescue of α-synuclein toxicity requires synaptic vesicle glycoprotein 2

BackgroundParkinsons disease (PD) is characterized by -synuclein aggregation and loss of dopamine (DA) neurons in the substantia nigra. Risk of PD arises due to a combination of genetic and environmental factors, which may interact, termed gene-environment (GxE) interactions. An inverse association between smoking and risk of PD is well-established, and a previous genome-wide GxE interaction study identified genetic variation in the synaptic-vesicle glycoprotein 2C (SV2C) locus as an important mediator of the degree to which smoking is inversely associated with PD. ObjectiveWe sought to determine the mechanism of the smoking-SV2C interaction in a Drosophila model of PD. MethodsFlies expressing human -synuclein in all neurons develop the hallmarks of PD, including motor dysfunction, loss of DA neurons, and formation of -synuclein inclusions. We assessed the effects of increasing doses of nicotine on these parameters of neurodegeneration, in the presence or absence of SV2 knockdown. Results-synuclein-expressing flies treated with nicotine had improvement in locomotion, DA neuron counts, and in -synuclein aggregation. However, in -synuclein-expressing flies in which Drosophila orthologs of SV2 were knocked down, nicotine failed to rescue neurodegeneration. ConclusionsThis work confirms a GxE interaction between nicotine and SV2, defines a role for this interaction in -synuclein proteostasis, and suggests that future clinical trials on nicotine should consider genetic variation in SV2C. Further, this provides proof of concept that our model can be used for mechanistic study of GxE, paving the way for investigation of additional GxE interactions or identification of novel GxE.

neuroscience↗

bioRxiv2021

Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment.

Alexander disease (AxD) is a devastating leukodystrophy caused by gain of function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report we introduce a new rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, widespread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with approximately 15 % dying of unknown cause between 6 to 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long lasting suppression, reverses GFAP pathology, and depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. This is the first report of an animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease. We use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease.

neuroscience↗