Data from: Revisiting protein aggregation as pathogenic in sporadic Parkinson's and Alzheimer's diseases

Publication Date

2-12-2019

Abstract

The gold standard for a definitive diagnosis of Parkinson's disease (PD) is the pathologic finding of aggregated alpha-synuclein into Lewy bodies and for Alzheimer's disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinico-pathologic-based nosology is the assumption that pathological protein aggregation at autopsy reflect pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated alpha-synuclein in SNCA gene multiplication or aggregated -amyloid in APP mutations), their near universality at postmortem in sporadic PD and AD suggests they may alternatively represent common outcomes from upstream mechanisms or compensatory responses to cellular stress in order to delay cell death. These three conceptual frameworks of protein aggregation (pathogenic, epiphenomenon, protective) are difficult to resolve because of the inability to probe brain tissue in real time. Whereas animal models, in which neither PD nor AD occur in natural states, consistently support a pathogenic role of protein aggregation, indirect evidence from human studies does not. We hypothesize that (1) current biomarkers of protein aggregates may be relevant to common pathology but not to subgroup pathogenesis, and (2) disease-modifying treatments targeting oligomers or fibrils might be futile or deleterious because these proteins are epiphenomena or protective in the human brain under molecular stress. Future precision-medicine efforts for molecular targeting of neurodegenerative diseases may require analyses not anchored on current clinico-pathologic criteria but instead on biological signals generated from large deeply-phenotyped aging populations or from smaller but well-defined genetic-molecular cohorts.

Keywords

disease modifying treatments, Alzheimer's disease, Clinical Trials, Parkinson's disease

Repository

Dryad

Distribution License

CC0 1.0 Universal - No copyright; this work is in the public domain

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