Autophagy in polyglutamine disease: Imposing order on disorder or contributing to the chaos?

Molecular and Cellular Neurosciences
Constanza J Cortes, Albert R La Spada

Abstract

Autophagy is an essential, fundamentally important catabolic pathway in which double membrane-bound vesicles form in the cytosol and encircle macromolecules and organelles to permit their degradation after fusion with lysosomes. More than a decade of research has revealed that autophagy is required for normal central nervous system (CNS) function and plays a central role in maintaining protein and organelle quality controls in neurons. Neurodegenerative diseases occur when misfolded proteins accumulate and disrupt normal cellular processes, and autophagy has emerged as a key arbiter of the cell's homeostatic response to this threat. One class of inherited neurodegenerative disease is known as the CAG/polyglutamine repeat disorders, and these diseases all result from the expansion of a CAG repeat tract in the coding regions of distinct genes. Polyglutamine (polyQ) repeat diseases result in the production polyQ-expanded proteins that misfold to form inclusions or aggregates that challenge the main cellular proteostasis system of the cell, the ubiquitin proteasome system (UPS). The UPS cannot efficiently degrade polyQ-expanded disease proteins, and components of the UPS are enriched in polyQ disease aggregate bodies found in degen...Continue Reading

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