期刊
AUTOPHAGY
卷 14, 期 8, 页码 1404-1418出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2018.1461294
关键词
Aging; alpha-synuclein; autophagy; lewy body disease; MAPT; mitochondria; mitophagy; PARK2; parkin; parkinson disease; phospho-ubiquitin; PINK1; SNCA; tau; ubiquitin
类别
资金
- National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS) [R01 NS085070]
- Michael J. Fox Foundation for Parkinson Research
- Foundation for Mitochondrial Medicine
- Mayo Clinic Neuroscience Focused Research Team (NFRT) Award
- Mayo Clinic Center for Individualized Medicine (CIM)
- Mayo Clinic Center for Center for Biomedical Discovery (CBD)
- Marriott Family Foundation
- Gerstner Family Foundation Career Development Award
- NIH/NINDS [P50 NS072187, R01 NS078086, U54 NS100693]
- Mayo Clinic Alzheimer Disease Research Center (ADRC)
- American Parkinson Disease Association (APDA)
- Younkin Scholar Program
- APDA
- Allergan Medical Educational Grant
- Jaye F. and Betty F. Dyer Foundation Fellowship in progressive supranuclear palsy research
- Max Kade Foundation postdoctoral fellowship
- Mayo Clinic Center for Regenerative Medicine (CRM)
- Mangurian Foundation for Lewy body research
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS085070, P50NS072187, U54NS100693] Funding Source: NIH RePORTER
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据