Enhanced Hyaluronan Signaling and Autophagy Dysfunction by VPS35 D620N

Abir A Rahman¹, Alejandro Soto-Avellaneda¹, Hyun Yong Jin²

¹Department of Biological Sciences, Boise State University, Boise, ID 83725, USA; Biomolecular Ph.D. Program, Boise State University, Boise, ID 83725, USA.

|June 17, 2020

Summary

Parkinson's disease (PD) involves autophagy defects linked to VPS35 mutations. High molecular weight hyaluronan (HA) and its receptors, CD44 and HMMR, disrupt autophagy, with HMMR knockdown rescuing PD-related autophagy dysfunction.

Area of Science:

Neuroscience
Cell Biology
Molecular Biology

Background:

Parkinson's disease (PD) motor symptoms stem from dopaminergic neuron loss, with impaired autophagy a key factor.
A familial PD mutation (VPS35 D620N) inhibits autophagy, prompting investigation into underlying signaling pathways.

Purpose of the Study:

To identify signaling pathways responsible for autophagy defects in Parkinson's disease.
To investigate the role of extracellular matrix (ECM) components and their receptors in PD-related autophagy dysfunction.

Main Methods:

RNA sequencing (RNA-Seq) of wild-type and VPS35 D620N-mutant cells.
Analysis of extracellular matrix (ECM)-receptor interactions and PI3K-AKT signaling.
Assessment of hyaluronan (HA) molecular weight effects on autophagy.
Validation of CD44 and HMMR expression and functional impact via knockdown.

Main Results:

VPS35 D620N expression altered transcriptomes, implicating ECM-receptor interactions and PI3K-AKT signaling.
High molecular weight HA inhibited autophagy, and VPS35 D620N enhanced HA-AKT signaling.
Differential expression of CD44 and HMMR isoforms was observed in VPS35 D620N cells.
HMMR knockdown, but not CD44, rescued autophagy dysfunction caused by VPS35 D620N.

Conclusions:

Hyaluronan (HA) signaling via CD44 and HMMR, particularly HMMR, plays a role in Parkinson's disease pathogenesis.
Targeting HMMR may offer a therapeutic strategy for restoring autophagy function in PD.

Keywords:

CD44 HMMR VPS35 autophagyt extracellular matrix

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Related Experiment Videos

Enhanced Hyaluronan Signaling and Autophagy Dysfunction by VPS35 D620N

Area of Science:

Background:

Purpose of the Study:

Main Methods:

Main Results:

Conclusions:

Related Concept Videos

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