# Mechanisms Regulating Neuronal Specific Proteasomes in Neurodegeneration

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2022 · $409,375

## Abstract

Proteasomes are essential for protein homeostasis and proper neuronal function throughout life. This new
application focuses on studying a newly discovered neuronal specific abundant proteasome complex and its
link to neuronal function in health and aging related neurodegenerative disease. Based on extensive original
findings, our central hypothesis is that neuronal activity promotes the degradation of newly synthesized
proteins through a transmembrane-like proteasome complex in order to rapidly generate biologically
meaningful peptides that are critical for normal nervous system function and appear protective against
neurodegenerative processes. The rationale for the proposed research is that nothing is known about this new
form of protein homeostasis and further understanding is critical in providing vital insight into neuronal
functions mediated by protein degradation. Given the critical importance of protein degradation to human
health, the long-range objective of the proposed research is to understand the regulation and function of this
degradation program and to apply this knowledge to the detection and eventual treatment of cognitive
disorders. Specifically: Aim 1. To identify and study molecular components required for NMP complex
assembly and function, to test our hypothesis that a glycoprotein mediates transmembrane like association
of the proteasome in the neuronal plasma membrane, which is critical for promoting NMP mediated peptide
release and is in part controlled by the disease causing β–amyloid protein; Aim 2. To identify and study
specific NMP peptide-receptor interactions relevant to neuronal signaling, to test our hypothesis that
distinct amino acid sequences within NMP substrates are critical for NMP dependent degradation into unique
peptides that activate NMDAR dependent neuronal signaling and that this interferes with Aβ induced
pathologies; Aim 3. To investigate NMP relevance to neuronal physiology in healthy and diseased
brains, to test our hypothesis that inhibition of NMP function affects neuronal physiology and is relevant to
nervous system aging and neurodegenerative decline.

## Key facts

- **NIH application ID:** 10328548
- **Project number:** 5R01NS110754-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** SETH S MARGOLIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2019-03-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328548

## Citation

> US National Institutes of Health, RePORTER application 10328548, Mechanisms Regulating Neuronal Specific Proteasomes in Neurodegeneration (5R01NS110754-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10328548. Licensed CC0.

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