# MOLECULAR MECHANISMS OF NEUROPROTECTION IN POLYGLUTAMINE-DEPENDENT DEGENERATION > **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2024 · $489,222 ## Abstract PROJECT SUMMARY The goal of this resubmitted, competitive renewal R01 application is to execute an unprecedented, com- prehensive, parallel and rigorous examination of the processing of each polyglutamine (polyQ) disease protein through a novel, isogenic series of transgenic animals and approaches that span Drosophila ge- netics, physiology, mass spectrometry, mammalian cell biology and biochemistry. The polyQ family of proteins is linked to nine incurable neurodegenerative maladies: Spinocerebellar Ataxias (SCAs) 1, 2, 3, 6, 7 and 17, Huntington's disease, Dentatorubral-pallidoluysian atrophy and Kennedy's disease. While previous research yielded impactful insights into individual polyQ diseases, we lack a “birds-eye view” of the disease collective, which includes a concurrent analysis of the cellular processes key to the initiation and progression common to each polyQ disorder. Here, we propose to uncover the role of shared and distinct pathways in polyQ protein quality control. By the end of this proposed work, the field will have a comparative and mechanistic blueprint on how each polyQ protein is controlled and degraded in vivo. What we propose constitutes a rational and natural progression of the work that we conducted in prior cycles of this R01 award (04/2014-02/2023; currently in NCE). Based on our extensive work, we propose the hypothesis that polyQ diseases fall within distinct sub-categories of protein handling and toxicity, providing both a central- ized understanding of polyQ disease biology as well as establishing shared points of neuroprotection among these incurable disorders. We recently generated an isogenic series of transgenic flies to model the family of polyQ diseases. Each line contains the full-length human disease protein. Transgenes are integrated into a `safe harbor' site in the fly genome, are in the same orientation and consist of a single inserted copy. Through targeted genetic screens and hypothesis-based experimental design using this innovative series, we found overlapping components of protein quality control and related factors that serve to regulate several polyQ disease proteins; we also ob- served distinct regulatory processes that selectively affect some polyQ proteins, but not others. Now, we seek to expand on our observations to decipher the underlying mechanisms across the entire spec- trum of polyQ diseases by targeting key processes as well as focusing on individual cellular components. To bring additional relevance and physiological significance to our studies in Drosophila, we will complement our investigations with iNeuronal cultures differentiated into relevant cell populations. Assessments including fly morphology, mobility, longevity, genetics, mass spectrometry, cell biology and biochemistry will provide action- able information on the role of key cellular components involved in the degradation of polyQ proteins and their toxicity in an intact, multicellular organism and in the mammalian cell... ## Key facts - **NIH application ID:** 10817357 - **Project number:** 2R01NS086778-10A1 - **Recipient organization:** WAYNE STATE UNIVERSITY - **Principal Investigator:** Sokol Todi - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $489,222 - **Award type:** 2 - **Project period:** 2014-04-01 → 2028-11-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10817357 ## Citation > US National Institutes of Health, RePORTER application 10817357, MOLECULAR MECHANISMS OF NEUROPROTECTION IN POLYGLUTAMINE-DEPENDENT DEGENERATION (2R01NS086778-10A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10817357. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*