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2018-08-01

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/140074

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

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https://doi.org/10.1080/15548627.2018.1461294

Resum

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.

Matèries

Envelliment, Autofàgia, Mitocondris, Malaltia de Parkinson, Ubiqüitina

Matèries (anglès)

Aging, Autophagy, Mitochondria, Parkinson's disease, Ubiquitin

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Articles publicats en revistes (Patologia i Terapèutica Experimental)

Citació

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. Age- and disease-dependent increase of the mitophagy marker phospho-ubiquitin in normal aging and Lewy body disease. _Autophagy_. 2018. Vol. 14, núm. 8, pàgs. 1404-1418. [consulta: 13 de gener de 2026]. ISSN: 1554-8627. [Disponible a: https://hdl.handle.net/2445/140074]

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