Biology subjects

Prifti, M. V.

Publications and source records attributed to Prifti, M. V..

5 recordsLinked to original sources

bioRxiv2026

Androgen Receptor SUMO site mutations ameliorate toxicity in Drosophila models of SBMA

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the androgen receptor (AR) gene that produces a toxic, polyglutamine-expanded protein. SBMA is part of a broader class of polyglutamine (polyQ) diseases characterized by protein misfolding, aggregation, and progressive neuronal dysfunction, for which no disease-modifying therapies exist. Post-translational modification of AR, including SUMOylation, is an important regulator of its transcriptional activity, stability, and cellular localization. Disease protein modification by SUMO is implicated in various neurodegenerative diseases and can influence protein aggregation and toxicity in polyQ disorders. Prior studies suggest that preventing AR SUMOylation positively modifies disease phenotypes. Here, we generated Drosophila models expressing polyQ-expanded human AR in which the canonical SUMO acceptor lysine sites were mutated into arginines to prevent SUMOylation of AR. Using tissue-specific expression in neurons and muscle, we assessed effects on lifespan, motor behavior, AR localization, and gene expression. Mutation of AR SUMOylation sites leads to improvements in longevity when expressed in muscle. Effects on motor performance were more limited. Transcriptomic analysis revealed tissue-specific effects of AR SUMO-site mutation, with enrichment of immune, metabolic, and defense-related processes in heads, but limited enrichment in thoraces. In both tissues, a subset of genes altered by AR SUMO-site mutation showed expression changes opposing those associated with polyQ expansion. These findings support a modulatory role for SUMOylation in SBMA pathogenesis and highlight post-translational regulation of AR as a potential therapeutic avenue requiring further investigation.

neuroscience↗

bioRxiv2026

Polyglutamine-expanded TBP rewires neuronal and muscle proteomes beyond transcription in a Drosophila model of SCA17

Spinocerebellar ataxia type 17 (SCA17) is an age-related neurodegenerative disorder caused by polyglutamine expansion in the TATA-binding protein (TBP). TBP is a core transcription factor, but pathogenic polyglutamine expansion likely rewires cellular programs beyond transcription. Here, we utilized Drosophila strains that express wild-type (WT) or pathogenic (SCA17) TBP in neurons or skeletal muscle, which we analyzed vs. controls via TMT mass spectrometry, profiling of eight post-translational modifications, and RNA-seq. Shared TBP-WT and TBP-SCA17 responses predominated, impacting ribosomes and mitochondria while repressing innate immunity. Disease-specific effects were narrower and tissue-dependent: SCA17 activated xenobiotic, retinoid, and glutathione-redox pathways in the CNS, but attenuated anabolism in muscle compared to TBP-WT. Many proteomic changes occurred independently of mRNA changes, implicating post-transcriptional mechanisms. Knockdown of select SCA17-regulated proteins reduced cytotoxicity, validating omics-identified modifiers of SCA17 pathology. These findings distinguish shared TBP dosage effects from disease-linked, tissue-specific polyglutamine responses and identify evolutionarily conserved targets for SCA17.

neuroscience↗

bioRxiv2024

Insights into Dentatorubral-Pallidoluysian Atrophy from a new Drosophila model of disease

Dentatorubral-pallidoluysian atrophy (DRPLA) is a neurodegenerative disorder that presents with ataxia, dementia and epilepsy. As a member of the polyglutamine family of diseases, DRPLA is caused by abnormal CAG triplet expansion beyond 48 repeats in the protein-coding region of ATROPHIN 1 (ATN1), a transcriptional co-repressor. To better understand DRPLA, we generated new Drosophila lines that express full-length, human ATN1 with a normal (Q7) or pathogenic (Q88) repeat. Expression of ATN1 is toxic, with the polyglutamine-expanded version being consistently more problematic than wild-type ATN1. Fly motility, longevity and internal structures are negatively impacted by pathogenic ATN1. RNA-seq identified altered protein quality control and immune pathways in the presence of pathogenic ATN1. Based on these data, we conducted genetic experiments that confirmed the role of protein quality control components that ameliorate or exacerbate ATN1 toxicity. Hsc70-3, a chaperone, arose as a likely suppressor of toxicity. VCP (a proteasome-related AAA ATPase), Rpn11 (a proteasome-related deubiquitinase) and select DnaJ proteins (co-chaperones) were inconsistently protective, depending on the tissues where they were expressed. Lastly, informed by RNA-seq data that exercise-related genes may also be involved in this model of DRPLA, we conducted short-term exercise, which improved overall fly motility. This new model of DRPLA will prove important to understanding this understudied disease and will help to identify therapeutic targets for it.

neuroscience↗

bioRxiv2023

Progressive degeneration in a new Drosophila model of Spinocerebellar Ataxia type 7

Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder resulting from abnormal expansion of polyglutamine (polyQ) in its disease protein, ataxin-7 (ATXN7). ATXN7 is part of Spt-Ada-Gcn5 acetyltransferase (SAGA), an evolutionarily conserved transcriptional coactivation complex with critical roles in chromatin remodeling, cell signaling, neurodifferentiation, mitochondrial health and autophagy. SCA7 is dominantly inherited and characterized by genetic anticipation and high repeat-length instability. Patients with SCA7 experience progressive ataxia, atrophy, spasticity, and blindness. There is currently no cure for SCA7, and therapies are aimed at alleviating symptoms to increase quality of life. Here, we report novel Drosophila lines of SCA7 with polyQ repeats in wild-type and human disease patient range. We find that ATXN7 expression has age- and polyQ repeat length-dependent reduction in survival and retinal instability, concomitant with increased ATXN7 protein aggregation. These new lines will provide important insight on disease progression that can be used in the future to identify therapeutic targets for SCA7 patients.

neuroscience↗

bioRxiv2021

Endurance exercise ameliorates phenotypes in Drosophila models of Spinocerebellar Ataxias

Endurance exercise is a potent intervention with widespread benefits proven to reduce disease incidence and impact across species. While endurance exercise supports neural plasticity, enhanced memory, and reduced neurodegeneration, less is known about the effect of chronic exercise on the progression of movement disorders such as ataxias. Here, we focused on three different types of ataxias, Spinocerebellar Ataxias Type (SCAs) 2, 3, and 6, belonging to the polyglutamine (polyQ) family of neurodegenerative disorders. In Drosophila models of these SCAs, flies progressively lose motor function. Here, we observe marked protection of speed and endurance in exercised SCA2 flies and modest protection in exercised SCA6 models, while no benefit is observed in SCA3 flies. Causative protein levels are reduced in SCA2 flies after chronic exercise, but not in SCA3 models, linking protein levels to exercise-based benefits. Additional investigations indicate that the exercise-inducible protein, Sestrin (Sesn) suppresses mobility decline and improves early death in SCA2 flies, even without exercise, coincident with disease protein level reduction and increased autophagic flux. These improvements depend on previously established functions of Sesn that reduce oxidative damage and modulate mTOR activity. Our study suggests differential responses of polyQ SCAs to exercise, highlighting the potential for more extensive application of exercise-based therapies in the prevention of polyQ neurodegeneration. Defining the mechanisms by which endurance exercise suppresses polyQ SCAs will open the door for more effective treatment for these diseases.

neuroscience↗