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

Xu Hou, Fabienne C. Fiesel, Dominika Truban, Monica Castanedes Casey, Wen lang Lin, Alexandra I. Soto, Pawel Tacik, Linda G. Rousseau, Nancy N. Diehl, Michael G. Heckman, Oswaldo Lorenzo-Betancor, Isidre Ferrer, José M. Arbelo, John C. Steele, Matthew J. Farrer, Mario Cornejo-Olivas, Luis Torres, Ignacio F. Mata, Neill R. Graff-Radford, Zbigniew K. WszolekOwen A. Ross, Melissa E. Murray, Dennis W. Dickson, Wolfdieter Springer

Research output: Contribution to journalArticle

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1404-1418
Number of pages15
JournalAutophagy
Volume14
Issue number8
DOIs
StatePublished - Aug 3 2018

Keywords

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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