# Elucidating cellular mechanisms underlying neurodegeneration

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2023 · $575,736

## Abstract

Giant axonal neuropathy (GAN) is an early-onset, autosomal recessive neurodegenerative disease that
impacts the central and peripheral nervous systems. Pathologically, GAN is characterized by the
disorganization and aggregation of intermediate filaments (IF). Formed from self-assembling subunits, the IF
network spans the cell from the nucleus to the periphery. In GAN, many cell types show abnormalities in the
organization of IF, but neurons clearly bear the brunt of the pathology. Axons swell with the accumulation of
neuronal IF, and degenerate to cause the neurological symptoms of GAN. The gene mutated in GAN encodes
gigaxonin, a protein that belongs to the BTB/Kelch family of E3 ligase-like adaptor proteins. These proteins
typically play a role in ubiquitin-proteasome mediated protein degradation. Based on our own data that GAN
degrades neuronal IFs, we hypothesize that neurofilament aggregation creates steric roadblocks in neurites
that interfere with intracellular transport of organelles such as mitochondria and lysosomes, resulting in
downstream pathology. Furthermore, our preliminary data suggest gigaxonin plays a direct role in autophagy
via degradation of other substrates. We hypothesize that the disruption of this critical process exacerbates
GAN neuropathology by dysregulation of protein and organellar quality control. This proposal comprehensively
tests these models; thus the overall goal of our research is to understand the cellular pathogenesis of GAN
with a view to inspiring novel treatment strategies.

## Key facts

- **NIH application ID:** 10647869
- **Project number:** 5R01NS127204-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Puneet Opal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $575,736
- **Award type:** 5
- **Project period:** 2022-06-17 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10647869

## Citation

> US National Institutes of Health, RePORTER application 10647869, Elucidating cellular mechanisms underlying neurodegeneration (5R01NS127204-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10647869. Licensed CC0.

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