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A common feature of neurodegenerative disease is the accumulation of aggregated proteins. While the significance of these structures in pathogenesis is debated, the removal of aggregation-prone proteins may represent a means to counter neuronal dysfunction. Increasing evidence has implicated macroautophagy in the clearance of aggregation-prone proteins in a variety of neurodegenerative disorders. Macroautophagy involves the sequestration of cytoplasmic materials into double-membrane structures that are delivered to lysosomes for degradation. This review provides an overview of the role of macroautophagy in neurodegenerative disorders, with emphasis on aggrephagy, the selective macroautophagy of aggregated proteins. We will examine the evidence for macroautophagic degradation of aggregation-prone proteins, including polyglutamine-expanded proteins, alpha-synuclein, amyloid-beta, prion, TDP-43, and SOD1. The content and localization of distinctive types of aggregates may influence their degradation, and there is evidence that macroautophagy may be compromised in neurodegenerative disease states. Pharmacological interventions to upregulate macroautophagy are being explored in model systems, but their lack of specificity highlights continued need for a better understanding of the molecular mechanisms underlying removal of selective protein cargo. |
