http://www.frontiersin.org/neuroscience/agingneuroscience/paper/10.3389/fnagi.2010.00024/

Vollständiger Abstract

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Protein aggregation and proteostasis decline are central features of aging and neurodegenerative disease, arising from progressive impairment of protein quality-control systems and transitions into aggregation-prone states. During aging, diverse proteins, including metabolic and proteostasis-related factors, gradually accumulate in aggregated forms as proteostasis capacity declines. Although these aggregates often remain compatible with cellular function, increasing aggregate burden progressively challenges proteostasis resilience. Neurodegenerative diseases are characterized by the emergence and amplification of highly toxic, structurally ordered protein assemblies, including amyloid-β (Aβ) and tau, which exist along a continuum with broader age-associated proteome instability rather than as entirely distinct phenomena. Oxidative and metabolic imbalances promote non-enzymatic post-translational modifications (PTMs), including cysteine oxidation, S-nitrosylation, and carbonylation, which alter protein structure, impair degradation pathways, and facilitate misfolding and aggregation. Here, we compare oxidative PTM-driven aggregates observed during aging with disease-associated protein assemblies, highlighting both shared biophysical mechanisms and distinct pathological outcomes. We propose a threshold model in which the cumulative burden of oxidative PTMs, protein misfolding, and impaired clearance progressively erodes proteostasis capacity, increasing susceptibility to the emergence of selective, self-amplifying aggregates. By integrating intracellular quality-control systems with extracellular clearance pathways, including glymphatic and meningeal lymphatic networks, this framework provides a mechanistic perspective on how aggregate diversity evolves toward disease-associated pathology and suggests therapeutic strategies that combine aggregate-specific targeting with restoration of global proteostasis and clearance capacity.

Abstract: PubMed · Datensatz