Unlabelled: 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.
Abbreviations: BLBD: brainstem predominant Lewy body disease; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; DLB: dementia with Lewy bodies; DLBD: diffuse neocortical Lewy body disease; EOPD: early-onset Parkinson disease; GVB: granulovacuolar degeneration body; LB: Lewy body; LBD: Lewy body disease; mitoQC: mitochondrial quality control; nbM: nucleus basalis of Meynert; PD: Parkinson disease; PDD: Parkinson disease with dementia; p-S65-Ub: PINK1-phosphorylated serine 65 ubiquitin; SN: substantia nigra; TLBD: transitional Lewy body disease; Ub: ubiquitin.
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http://dx.doi.org/10.1080/15548627.2018.1461294 | DOI Listing |
Biomarkers that aid in early detection of neurodegeneration are needed to enable early symptomatic treatment and enable identification of people who may benefit from neuroprotective interventions. Increasing evidence suggests that sleep biomarkers may be useful, given the bi-directional relationship between sleep and neurodegeneration and the prominence of sleep disturbances and altered sleep architectural characteristics in several neurodegenerative disorders. This study aimed to demonstrate that sleep can accurately characterize specific neurodegenerative disorders (NDD).
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA.
Alzheimers Dement
December 2024
Djavad Mowafaghian Centre for Brain Health, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Alzheimers Dement
December 2024
Centre for Healthy Brain Ageing, Department of Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
Introduction: Neuropsychiatric symptoms (NPSs) are common in dementia with Lewy bodies (DLB) but their neurobiological mechanisms are poorly understood.
Methods: NPSs and cognition were assessed annually in participants (DLB n = 222; Alzheimer's disease [AD] n = 125) from the European DLB (E-DLB) Consortium, and plasma phosphorylated tau-181 (p-tau181) and p-tau231 concentrations were measured at baseline.
Results: Hallucinations, delusions, and depression were more common in DLB than in AD and, in a subgroup with longitudinal follow-up, persistent hallucinations and NPSs were associated with lower p-tau181 and p-tau231 in DLB.
Alzheimers Dement
December 2024
Banner Sun Health Research Institute and Banner Alzheimer's Institute, Banner Health, Sun City, Arizona, USA.
This special issue contains multiple articles related to the DETeCD-ADRD guideline.
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