Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein.
Parkinson’s disease
induced pluripotent stem cells
lysosomal storage disease
lysosomal stress
protein aggregation
proteomic stress
synucleinopathy
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
04 12 2019
04 12 2019
Historique:
received:
14
01
2019
revised:
05
06
2019
accepted:
30
08
2019
pubmed:
28
10
2019
medline:
24
3
2020
entrez:
26
10
2019
Statut:
ppublish
Résumé
Age-related neurodegenerative disorders are characterized by a slow, persistent accumulation of aggregated proteins. Although cells can elicit physiological responses to enhance cellular clearance and counteract accumulation, it is unclear how pathogenic proteins evade this process in disease. We find that Parkinson's disease α-synuclein perturbs the physiological response to lysosomal stress by impeding the SNARE protein ykt6. Cytosolic ykt6 is normally autoinhibited by a unique farnesyl-mediated regulatory mechanism; however, during lysosomal stress, it activates and redistributes into membranes to preferentially promote hydrolase trafficking and enhance cellular clearance. α-Synuclein aberrantly binds and deactivates ykt6 in patient-derived neurons, thereby disabling the lysosomal stress response and facilitating protein accumulation. Activating ykt6 by small-molecule farnesyltransferase inhibitors restores lysosomal activity and reduces α-synuclein in patient-derived neurons and mice. Our findings indicate that α-synuclein creates a permissive environment for aggregate persistence by inhibiting regulated cellular clearance and provide a therapeutic strategy to restore protein homeostasis by harnessing SNARE activity.
Identifiants
pubmed: 31648898
pii: S0896-6273(19)30774-3
doi: 10.1016/j.neuron.2019.09.001
pmc: PMC6895429
mid: NIHMS1539637
pii:
doi:
Substances chimiques
R-SNARE Proteins
0
YKT6 protein, human
0
alpha-Synuclein
0
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
869-884.e11Subventions
Organisme : NINDS NIH HHS
ID : R01 NS092823
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS118824
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS107770
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008152
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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