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http://hdl.handle.net/2445/140074
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 Autofàgia Mitocondris Malaltia de Parkinson Ubiqüitina Aging Autophagy Mitochondria Parkinson's disease Ubiquitin |
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: https://doi.org/10.1080/15548627.2018.1461294 |
It is part of: | Autophagy, 2018, vol. 14, num. 8, p. 1404-1418 |
URI: | http://hdl.handle.net/2445/140074 |
Related resource: | https://doi.org/10.1080/15548627.2018.1461294 |
ISSN: | 1554-8627 |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) |
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File | Description | Size | Format | |
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689453.pdf | 11.65 MB | Adobe PDF | View/Open |
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