Enhanced Hyaluronan Signaling and Autophagy Dysfunction by VPS35 D620N.
CD44
HMMR
VPS35
autophagyt
extracellular matrix
Journal
Neuroscience
ISSN: 1873-7544
Titre abrégé: Neuroscience
Pays: United States
ID NLM: 7605074
Informations de publication
Date de publication:
10 08 2020
10 08 2020
Historique:
received:
19
03
2020
revised:
03
06
2020
accepted:
05
06
2020
pubmed:
17
6
2020
medline:
15
5
2021
entrez:
17
6
2020
Statut:
ppublish
Résumé
The motor features of Parkinson's disease (PD) result from the loss of dopaminergic (DA) neurons in the substantia nigra with autophagy dysfunction being closely linked to this disease. A PD-causing familial mutation in VPS35 (D620N) has been reported to inhibit autophagy. In order to identify signaling pathways responsible for this autophagy defect, we performed an unbiased screen using RNA sequencing (RNA-Seq) of wild-type or VPS35 D620N-expressing retinoic acid-differentiated SH-SY5Y cells. We report that VPS35 D620N-expressing cells exhibit transcriptome changes indicative of alterations in extracellular matrix (ECM)-receptor interaction as well as PI3K-AKT signaling, a pathway known to regulate autophagy. Hyaluronan (HA) is a major component of brain ECM and signals via the ECM receptors CD44, a top RNA-Seq hit, and HA-mediated motility receptor (HMMR) to the autophagy-regulating PI3K-AKT pathway. We find that high (>950 kDa), but not low (15-40 kDa), molecular weight HA treatment inhibits autophagy. In addition, VPS35 D620N facilitated enhanced HA-AKT signaling. Transcriptomic assessment and validation of protein levels identified the differential expression of CD44 and HMMR isoforms in VPS35 D620N mutant cells. We report that knockdown of HMMR or CD44 results in upregulated autophagy in cells expressing wild-type VPS35. However, only HMMR knockdown resulted in rescue of autophagy dysfunction by VPS35 D620N indicating a potential pathogenic role for this receptor and HA signaling in Parkinson's disease.
Identifiants
pubmed: 32540366
pii: S0306-4522(20)30379-1
doi: 10.1016/j.neuroscience.2020.06.009
pmc: PMC7390708
mid: NIHMS1605444
pii:
doi:
Substances chimiques
Hyaluronan Receptors
0
VPS35 protein, human
0
Vesicular Transport Proteins
0
Hyaluronic Acid
9004-61-9
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
33-45Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM103408
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM109095
Pays : United States
Organisme : NINDS NIH HHS
ID : R15 NS096702
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.
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