Hou, XuFiesel, Fabienne C.Truban, DominikaCastanedes Casey, MonicaLin, Wen-langSoto, Alexandra I.Tacik, PawelRousseau, Linda G.Diehl, Nancy N.Heckman, Michael G.Lorenzo-Betancor, OswaldoFerrer, Isidro (Ferrer Abizanda)Arbelo, José M.Steele, John C.Farrer, Matthew J.Cornejo-Olivas, MariaTorres, LuisMata, Ignacio F.Graff-Radford, Neill R.Wszolek, Zbigniew K.Ross, Owen A.Murray, Melissa E.Dickson, Dennis W.Springer, Wolfdieter2019-09-162019-09-162018-08-011554-8627https://hdl.handle.net/2445/140074Although 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.15 p.application/pdfeng(c) Landes Bioscience , 2018EnvellimentAutofàgiaMitocondrisMalaltia de ParkinsonUbiqüitinaAgingAutophagyMitochondriaParkinson's diseaseUbiquitininfo:eu-repo/semantics/article6894532019-09-16info:eu-repo/semantics/openAccess29947276