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Autophagy. 2018;14(8):1404-1418. doi: 10.1080/15548627.2018.1461294. Epub 2018 Jul 28.

Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease.

Author information

1
a Department of Neuroscience , Mayo Clinic , Jacksonville , FL , USA.
2
b Mayo Clinic College of Medicine and Science , Mayo Clinic Graduate School of Biomedical Sciences , Jacksonville , FL , USA.
3
c Division of Biomedical Statistics and Informatics , Mayo Clinic , Jacksonville , FL , USA.
4
d Institut de Neuropatologia, Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge , Hospitalet del Llobregat , Barcelona , Spain.
5
e CIBERNED, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas , Instituto de Salud Carlos III , Spain.
6
f Parkinson's and Movement Disorders Unit, Department of Neurology , Hospital Universitario Insular de Gran Canaria , Las Palmas de Gran Canaria , Spain.
7
g Micronesian Health Study II , Tamuning , Guam.
8
h Department of Medical Genetics , University of British Columbia , Vancouver , BC , Canada.
9
i Northern Pacific Global Health Research Fellows Training Consortium , Bethesda , MD , USA.
10
j Neurogenetics Research Center , Instituto Nacional de Ciencias Neurologicas , Lima , Peru.
11
k Movement Disorders Unit , Instituto Nacional de Ciencias Neurologicas , Lima , Peru.
12
l Veterans Affairs Puget Sound Health Care System , University of Washington , Seattle , WA , USA.
13
m Department of Neurology , University of Washington , Seattle , WA , USA.
14
n Department of Neurology , Mayo Clinic , Jacksonville , FL , USA.

Abstract

Although exact causes of Parkinson disease (PD) remain enigmatic, mitochondrial dysfunction is increasingly appreciated as a key determinant of dopaminergic neuron susceptibility in both familial and sporadic PD. Two genes associated with recessive, early-onset PD encode the ubiquitin (Ub) kinase PINK1 and the E3 Ub ligase PRKN/PARK2/Parkin, which together orchestrate a protective mitochondrial quality control (mitoQC) pathway. Upon stress, both enzymes cooperatively identify and decorate damaged mitochondria with phosphorylated poly-Ub (p-S65-Ub) chains. This specific label is subsequently recognized by autophagy receptors that further facilitate mitochondrial degradation in lysosomes (mitophagy). Here, we analyzed human post-mortem brain specimens and identified distinct pools of p-S65-Ub-positive structures that partially colocalized with markers of mitochondria, autophagy, lysosomes and/or granulovacuolar degeneration bodies. We further quantified levels and distribution of the 'mitophagy tag' in 2 large cohorts of brain samples from normal aging and Lewy body disease (LBD) cases using unbiased digital pathology. Somatic p-S65-Ub structures independently increased with age and disease in distinct brain regions and enhanced levels in LBD brain were age- and Braak tangle stage-dependent. Additionally, we observed significant correlations of p-S65-Ub with LBs and neurofibrillary tangle levels in disease. The degree of co-existing p-S65-Ub signals and pathological PD hallmarks increased in the pre-mature stage, but decreased in the late stage of LB or tangle aggregation. Altogether, our study provides further evidence for a potential pathogenic overlap among different forms of PD and suggests that p-S65-Ub can serve as a biomarker for mitochondrial damage in aging and disease.

ABBREVIATIONS:

BLBD: brainstem predominant Lewy body disease; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DLB: dementia with Lewy bodies; DLBD: diffuse neocortical Lewy body disease; EOPD: early-onset Parkinson disease; GVB: granulovacuolar degeneration body; LB: Lewy body; LBD: Lewy body disease; mitoQC: mitochondrial quality control; nbM: nucleus basalis of Meynert; PD: Parkinson disease; PDD: Parkinson disease with dementia; p-S65-Ub: PINK1-phosphorylated serine 65 ubiquitin; SN: substantia nigra; TLBD: transitional Lewy body disease; Ub: ubiquitin.

KEYWORDS:

Aging; MAPT; PARK2; PINK1; SNCA; alpha-synuclein; autophagy; lewy body disease; mitochondria; mitophagy; parkin; parkinson disease; phospho-ubiquitin; tau; ubiquitin

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