@article{1a9304e9e9284c239716a74747c1d9a7,
title = "Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology",
abstract = "Introduction: 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.",
keywords = "Alzheimer's disease, PINK1, PRKN, Parkin, autophagy, granulovacuolar degeneration, lysosomes, mitochondria, mitophagy, tau, ubiquitin",
author = "Xu Hou and Watzlawik, {Jens O.} and Casey Cook and Liu, {Chia Chen} and Kang, {Silvia S.} and Lin, {Wen Lang} and Michael DeTure and Heckman, {Michael G.} and Diehl, {Nancy N.} and Al-Shaikh, {Fadi S.Hanna} and Walton, {Ronald L.} and Ross, {Owen A.} and Melrose, {Heather L.} and Nil{\"u}fer Ertekin-Taner and Guojun Bu and Leonard Petrucelli and Fryer, {John D.} and Murray, {Melissa E.} and Dickson, {Dennis W.} and Fiesel, {Fabienne C.} and Wolfdieter Springer",
note = "Funding Information: We are grateful to the patients and their families who made this study possible. We thank Monica Castanedes-Casey, Linda G. Rousseau, Virginia R. Phillips, Billie J. Matchett, and Sydney A. Labuzan from the Neuropathology Laboratory for processing human post-mortem tissues and the excellent technical support. We also thank Dr. Peter Davies from the Feinstein Institute for his generous contribution of p-tau antibodies. Funding Information: W.S. is partially supported by the National Institutes of Health National Institute on Aging (NIH/NIA) [R56 AG062556], National Institute of Neurological Disorders and Stroke (NIH/NINDS) [R01/RF1 NS085070 and U54 NS110435], the Department of Defense Congressionally Directed Medical Research Programs (CDMRP) [W81XWH‐17‐1‐0248], the Florida Department of Health ‐ Ed and Ethel Moore Alzheimer's Disease Research Program [9AZ10], the Michael J. Fox Foundation for Parkinson's Research (MJFF), and the Mayo Clinic Foundation and the Center for Biomedical Discovery (CBD). X.H. is supported by a pilot grant from the Mayo Clinic Alzheimer's Disease Research Center (ADRC) and a fellowship awarded by the American Parkinson Disease Association (APDA). F.C.F. is the recipient of fellowships from the Younkin Scholar Program and the APDA and is supported in part by the MJFF and a Gerstner Family Career Development Award from the Mayo Clinic Center for Individualized Medicine (CIM). L.P., C.C., and D.W.D. are supported by the NIH/NINDS [U54 NS100693] and L.P. is supported by NIH/NINDS [R35 NS097273]. G.B. is supported by NIH/NIA [R37 AG027924]. Publisher Copyright: {\textcopyright} 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",
year = "2021",
month = mar,
doi = "10.1002/alz.12198",
language = "English (US)",
volume = "17",
pages = "417--430",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "3",
}