# VPS35 D620N inhibits autophagy through disrupted hyaluronic acid-CD44 signaling

> **NIH NIH P20** · BOISE STATE UNIVERSITY · 2021 · $220,945

## Abstract

Project Summary - Morrison
Parkinson’s disease (PD) is the most common motor disease in the USA. The primary clinical motor symptoms
of PD result from loss of dopaminergic (DA) neurons in the substantia nigra with autophagy dysfunction being
closely linked to this disease. Autophagy is a cellular process responsible for degradation of organelles,
macromolecules, and protein aggregates. In PD, characteristic toxic protein aggregates of primarily alpha-
synuclein are believed to be substrates for autophagic removal and clearance by autophagy improves
preclinical model outcomes. Therefore, modulation of autophagy may be an effective strategy to combat PD.
Recently, a PD-causing mutation in VPS35 (D620N) was reported to block autophagy. However, preliminary
investigation by other groups into a causal mechanism was limited to canonical VPS35 protein interactors in a
cervical cancer cell line. To overcome these limitations, we performed an unbiased screen using RNA
sequencing (RNA seq) to identify key pathways affected in a widely used cellular model of PD. We have
identified alterations indicative of perturbed extracellular matrix (ECM)-receptor interaction as well as aberrant
AKT signaling, a downstream pathway known to regulate the induction of autophagy. Hyaluronic acid (HA) is
the major component of brain ECM and signals via CD44, an ECM receptor identified as a top hit by our RNA
Seq screen, to the autophagy regulating AKT-mTOR pathway, making this axis a prime candidate for
mediating the VPS35 D620N autophagy blockade. Furthermore, VPS35’s well-established role in the retromer
complex, a protein complex that directs plasma membrane receptor trafficking, suggests that altered trafficking
of CD44 by the VPS35 mutant may be responsible for the observed alteration of AKT pathway activation and
the subsequent repression of autophagy. The central hypothesis of this proposal is that VPS35 D620N blocks
autophagy through dysregulated hyaluronic acid-CD44 signaling by altered trafficking of CD44. We propose
testing our hypothesis by examining HA-CD44-AKT pathway activation in VPS35 mutant expressing cells;
validating the importance of this pathway by genetic and pharmacological rescue of the mutant phenotype; and
assessing whether aberrant CD44 activation leads to increased neuronal loss. Whether perturbed CD44
trafficking by VPS35 D620N underlies altered signaling will be determined.

## Key facts

- **NIH application ID:** 10226312
- **Project number:** 5P20GM109095-08
- **Recipient organization:** BOISE STATE UNIVERSITY
- **Principal Investigator:** Brad Edward Morrison
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $220,945
- **Award type:** 5
- **Project period:** 2014-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226312

## Citation

> US National Institutes of Health, RePORTER application 10226312, VPS35 D620N inhibits autophagy through disrupted hyaluronic acid-CD44 signaling (5P20GM109095-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226312. Licensed CC0.

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