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Title: Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease
Author: Hou, Xu
Fiesel, Fabienne C.
Truban, Dominika
Castanedes Casey, Monica
Lin, Wen-lang
Soto, Alexandra I.
Tacik, Pawel
Rousseau, Linda G.
Diehl, Nancy N.
Heckman, Michael G.
Lorenzo-Betancor, Oswaldo
Ferrer, Isidro (Ferrer Abizanda)
Arbelo, José M.
Steele, John C.
Farrer, Matthew J.
Cornejo-Olivas, Maria
Torres, Luis
Mata, Ignacio F.
Graff-Radford, Neill R.
Wszolek, Zbigniew K.
Ross, Owen A.
Murray, Melissa E.
Dickson, Dennis W.
Springer, Wolfdieter
Keywords: Envelliment
Malaltia de Parkinson
Parkinson's disease
Issue Date: 1-Aug-2018
Publisher: Landes Bioscience
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.
Note: Versió postprint del document publicat a:
It is part of: Autophagy, 2018, vol. 14, num. 8, p. 1404-1418
Related resource:
ISSN: 1554-8627
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)

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