Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology

Xu Hou; Jens O. Watzlawik; Casey Cook; Chia Chen Liu; Silvia S. Kang; Wen Lang Lin; Michael DeTure; Michael G. Heckman; Nancy N. Diehl; Fadi S.Hanna Al-Shaikh; Ronald L. Walton; Owen A. Ross; Heather L. Melrose; Nilüfer Ertekin-Taner; Guojun Bu; Leonard Petrucelli; John D. Fryer; Melissa E. Murray; Dennis W. Dickson; Fabienne C. Fiesel; Wolfdieter Springer

doi:10.1002/alz.12198

Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology

Xu Hou, Jens O. Watzlawik, Casey Cook, Chia Chen Liu, Silvia S. Kang, Wen Lang Lin, Michael DeTure, Michael G. Heckman, Nancy N. Diehl, Fadi S.Hanna Al-Shaikh, Ronald L. Walton, Owen A. Ross, Heather L. Melrose, Nilüfer Ertekin-Taner, Guojun Bu, Leonard Petrucelli, John D. Fryer, Melissa E. Murray, Dennis W. Dickson, Fabienne C. FieselWolfdieter Springer

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English (US)
Pages (from-to)	417-430
Number of pages	14
Journal	Alzheimer's and Dementia
Volume	17
Issue number	3
DOIs	https://doi.org/10.1002/alz.12198
State	Published - Mar 2021

Keywords

Alzheimer's disease
PINK1
PRKN
Parkin
autophagy
granulovacuolar degeneration
lysosomes
mitochondria
mitophagy
tau
ubiquitin

ASJC Scopus subject areas

Clinical Neurology
Geriatrics and Gerontology
Psychiatry and Mental health
Cellular and Molecular Neuroscience
Health Policy
Developmental Neuroscience
Epidemiology

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10.1002/alz.12198

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Hou, X., Watzlawik, J. O., Cook, C., Liu, C. C., Kang, S. S., Lin, W. L., DeTure, M., Heckman, M. G., Diehl, N. N., Al-Shaikh, F. S. H., Walton, R. L., Ross, O. A., Melrose, H. L., Ertekin-Taner, N., Bu, G., Petrucelli, L., Fryer, J. D., Murray, M. E., Dickson, D. W., ... Springer, W. (2021). Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology. Alzheimer's and Dementia, 17(3), 417-430. https://doi.org/10.1002/alz.12198

Hou, X, Watzlawik, JO, Cook, C , Liu, CC , Kang, SS, Lin, WL, DeTure, M, Heckman, MG, Diehl, NN, Al-Shaikh, FSH, Walton, RL, Ross, OA, Melrose, HL, Ertekin-Taner, N , Bu, G , Petrucelli, L, Fryer, JD, Murray, ME , Dickson, DW , Fiesel, FC & Springer, W 2021, 'Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology', Alzheimer's and Dementia, vol. 17, no. 3, pp. 417-430. https://doi.org/10.1002/alz.12198

@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 = "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",

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T1 - Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology

AU - Hou, Xu

AU - Watzlawik, Jens O.

AU - Cook, Casey

AU - Liu, Chia Chen

AU - Kang, Silvia S.

AU - Lin, Wen Lang

AU - DeTure, Michael

AU - Heckman, Michael G.

AU - Diehl, Nancy N.

AU - Al-Shaikh, Fadi S.Hanna

AU - Walton, Ronald L.

AU - Ross, Owen A.

AU - Melrose, Heather L.

AU - Ertekin-Taner, Nilüfer

AU - Bu, Guojun

AU - Petrucelli, Leonard

AU - Fryer, John D.

AU - Murray, Melissa E.

AU - Dickson, Dennis W.

AU - Fiesel, Fabienne C.

AU - Springer, Wolfdieter

PY - 2021/3

Y1 - 2021/3

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - PINK1

KW - PRKN

KW - Parkin

KW - autophagy

KW - granulovacuolar degeneration

KW - lysosomes

KW - mitochondria

KW - mitophagy

KW - tau

KW - ubiquitin

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AN - SCOPUS:85092188656

SN - 1552-5260

VL - 17

SP - 417

EP - 430

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 3

ER -

Mitophagy alterations in Alzheimer's disease are associated with granulovacuolar degeneration and early tau pathology

Abstract

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ASJC Scopus subject areas

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