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Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology
Author(s) -
Hou Xu,
Watzlawik Jens O.,
Cook Casey,
Liu ChiaChen,
Kang Silvia S.,
Lin WenLang,
DeTure Michael,
Heckman Michael G.,
Diehl Nancy N.,
AlShaikh Fadi S. Hanna,
Walton Ronald L.,
Ross Owen A.,
Melrose Heather L.,
ErtekinTaner Nilüfer,
Bu Guojun,
Petrucelli Leonard,
Fryer John D.,
Murray Melissa E.,
Dickson Dennis W.,
Fiesel Fabienne C.,
Springer Wolfdieter
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12198
Subject(s) - mitophagy , parkin , pink1 , autophagy , mitochondrion , biology , ubiquitin , ubiquitin ligase , microbiology and biotechnology , pathology , genetically modified mouse , parkinson's disease , transgene , medicine , disease , apoptosis , biochemistry , gene
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. Methods 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. Results 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. Discussion 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.