# Ataxin-2 complex proteins in neurodegeneration.

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $930,250

## Abstract

Project Summary/Abstract
This R35 proposal builds on experiments supported by a Javits R37 and a U01 CREATE Bio award and the
longstanding success of the principal investigator’s group leading from mechanistic discoveries in
spinocerebellar ataxias and translation to novel treatments, one of which is now in a phase 1 human trial
(BIIB105). The proposal’s unifying theme is a focus on RNA-binding proteins (RBPs) in the ATXN2-complex of
proteins that direct several aspects of RNA metabolism and that are prone to phase-separation and
aggregation. Building on our recent discoveries in polyglutamine-mediated neurodegeneration and neuronal
staufen-1 (STAU1) overabundance, we will apply multi-dimensional approaches to define novel pathogenic
mechanisms in their intersections with autophagy, the unfolded protein response (UPR), and with RNA
metabolism and transport. We postulate that these responses, while compensatory in the short term, become
maladaptive with sustained stress and that an RBP network response leads to progressive deterioration of
autophagic flux and amplification of apoptotic signaling. We have established a broad suite of innovative tools
and unique models in an exceptional research environment with established local and national collaborators
with whom we have shared resources over many years. Our approach has been to characterize cerebellar
degeneration at multiple time points using genome-wide transcriptomic, proteomic, morphologic, physiologic
and behavioral techniques. These foundations will allow us to rapidly progress from cellular to animal models
modifying dosage of specific genes in vitro and in vivo. We will now extend this approach from Purkinje cells to
spinal motor neurons enabling us to address fundamental issues of broad relevance to inherited and sporadic
neurodegenerative diseases. These topical issues include: the role of cytoplasmic RBPs, especially ATXN2
and STAU1, in response to nutrient, chemical and mutant protein stress; their regulation and interplay with
each other, and key proteins determining autophagic flux and the UPR; their overall effect on neuronal death;
and finally, their promise as therapeutic targets using small molecules and RNA-directed therapies. R35
funding will allow us to identify novel functions of proteins in the ATXN2-complex in neurodegeneration and
define shared features across different neurodegenerative diseases with particular relevance not only to
inherited, but also to sporadic forms of ataxia and motor neuron disease. The broad scope of our proposed
studies will enable participation of scientists with diverse backgrounds in a laboratory and departmental culture
of inclusivity and diversity. With our established commitment to reproducibility of animal models and gene
targeting approaches, the novel mechanistic insights hold promise for translation into developing novel
treatments for neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10450573
- **Project number:** 1R35NS127253-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Stefan M. PULST
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $930,250
- **Award type:** 1
- **Project period:** 2022-05-01 → 2030-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450573

## Citation

> US National Institutes of Health, RePORTER application 10450573, Ataxin-2 complex proteins in neurodegeneration. (1R35NS127253-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10450573. Licensed CC0.

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