Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology.
Alzheimer's disease
PINK1
PRKN
Parkin
autophagy
granulovacuolar degeneration
lysosomes
mitochondria
mitophagy
tau
ubiquitin
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
08 Oct 2020
08 Oct 2020
Historique:
received:
20
03
2020
revised:
26
08
2020
accepted:
30
08
2020
entrez:
22
10
2020
pubmed:
23
10
2020
medline:
23
10
2020
Statut:
aheadofprint
Résumé
The cytoprotective PTEN-induced kinase 1 (PINK1)-parkin RBR E3 ubiquitin protein ligase (PRKN) pathway selectively labels damaged mitochondria with phosphorylated ubiquitin (pS65-Ub) for their autophagic removal (mitophagy). Because dysfunctions of mitochondria and degradation pathways are early features of Alzheimer's disease (AD), mitophagy impairments may contribute to the pathogenesis. Morphology, levels, and distribution of the mitophagy tag pS65-Ub were evaluated by biochemical analyses combined with tissue and single cell imaging in AD autopsy brain and in transgenic mouse models. Analyses revealed significant increases of pS65-Ub levels in AD brain, which strongly correlated with granulovacuolar degeneration (GVD) and early phospho-tau deposits, but were independent of amyloid beta pathology. Single cell analyses revealed predominant co-localization of pS65-Ub with mitochondria, GVD bodies, and/or lysosomes depending on the brain region analyzed. Our study highlights mitophagy alterations in AD that are associated with early tau pathology, and suggests that distinct mitochondrial, autophagic, and/or lysosomal failure may contribute to the selective vulnerability in disease.
Identifiants
pubmed: 33090691
doi: 10.1002/alz.12198
pmc: PMC8048674
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIA NIH HHS
ID : R01 AG063780
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061796
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG062677
Pays : United States
Organisme : NIA NIH HHS
ID : R56 AG062556
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS110435
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS085070
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG046139
Pays : United States
Informations de copyright
© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
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Alzheimers Dement. 2020 Oct 8;:
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