# Mechanisms of neurodegenerative diseases: intersections with ubiquitin pathways

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $1,055,075

## Abstract

This R35 proposal builds on the principal investigator’s longstanding success seeking the causes of age-
related neurodegenerative diseases and developing treatments for these devastating and largely fatal
disorders. The proposal’s unifying theme is a focus on proteins that participate in ubiquitin-linked quality control
pathways and that are prone, in neurodegenerative diseases, to phase-separate and aggregate. Building on
our recent discoveries in polyglutamine-mediated neurodegeneration and brain-expressed ubiquilins (a class of
proteins implicated in various neurodegenerative diseases), we will apply multi-scalar approaches to define
pathogenic mechanisms, emphasizing intersections with ubiquitin-dependent pathways in the search for novel
therapeutic targets. The importance of ubiquitin in the nervous system extends far beyond its classically
defined degradative role in the ubiquitin-proteasome system. But how the broader ubiquitin signaling system is
impaired by, or activated in response to, diseases of the nervous system represents a significant gap in current
knowledge. Leveraging a broad suite of innovative tools/models and an exceptional research environment, we
will address fundamental issues of broad relevance to age-related neurodegeneration. These topical issues
include: the impact of altered ubiquitin signaling in the nucleus; the contribution of altered ubiquitin
homeostasis to selective cell type and regional vulnerability; and the relationship between mutation-induced
changes in phase transitions undertaken by disease proteins, altered function in ubiquitin-linked pathways, and
toxicity in the nervous system. The discoveries we make through the R35 will help define the complex
biological roles of ubiquitin in diseases of the nervous system, highlight potential shared elements of disease
pathogenesis, and identify promising therapeutic targets that could drive the development of treatments for
neurodegenerative disorders.

## Key facts

- **NIH application ID:** 10834112
- **Project number:** 5R35NS122302-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Henry L Paulson
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,055,075
- **Award type:** 5
- **Project period:** 2021-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834112

## Citation

> US National Institutes of Health, RePORTER application 10834112, Mechanisms of neurodegenerative diseases: intersections with ubiquitin pathways (5R35NS122302-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10834112. Licensed CC0.

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