The many faces of autophagy dysfunction in Huntington's disease: from mechanism to therapy

Abstract

Autophagy is the cellular process by which proteins, macromolecules, and organelles are targeted to and degraded by the lysosome. Given that neurodegenerative diseases involve the production of misfolded proteins that cannot be degraded by the protein quality-control systems of the cell, the autophagy pathway is now the focus of intense scrutiny, because autophagy is primarily responsible for maintaining normal cellular proteostasis in the central nervous system (CNS). Huntington's disease (HD) is an inherited CAG-polyglutamine repeat disorder, resulting from the production and accumulation of misfolded huntingtin (Htt) protein. HD shares key features with common neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD) and, thus, belongs to a large class of disorders known as neurodegenerative proteinopathies. Multiple independent lines of research have documented alterations in autophagy function in HD, and numerous studies have demonstrated a potential role for autophagy modulation as a therapeutic intervention. In this review, we consider the evidence for autophagy dysfunction in HD, and delineate different targets and mechanistic pathways that might account for the autophagy abnormalities detected in HD. We assess the utility of autophagy modulation as a treatment modality in HD, and suggest guidelines and caveats for future therapy development directed at the autophagy pathway in HD and related disorders.

Figure 1

Different molecular mechanisms account for autophagy pathway dysfunction in Huntington's disease (HD). In HD, a polyglutamine-expanded huntingtin (polyQ-Htt) protein is produced and accumulates in cells. The misfoldedpolyQ-htt elicits an endoplasmic reticulum (ER) stress response (A), and through direct inhibition of the ER-associated degradation pathway, impairment of ER-to-Golgi trafficking, and disruption of ER and mitochondrial calcium homeostasis, polyQ-htt ultimately yields ER stress-induced activation of the macroautophagy pathway. PolyQ-htt can sequester mammalian target of rapamycin (mTOR), resulting in disinhibition of macroautophagy; however, macroautophagy functions abnormally in HD, because the mutant polyQ-htt protein prevents recognition and loading of cargo into developing autophagosomes, resulting in an accumulation of autophagic vesicles (AVs) that are relatively empty, in terms of substrates for degradation (B). Lysosomal enzyme activity is reduced in HD, possibly because of an increased burden of reactive oxygen species (ROS), given that HD cells contain markedly increased numbers of lysosomes containing nondegradedlipofuscin (B). PolyQ-htt interacts excessively with Hsc70 and the lysosomal translocation machinery, resulting in diminished chaperone-mediated autophagy function in HD (C). As the amino-terminal fragment of polyQ-htt enters the nucleus, it has been shown to interfere with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α), a transcriptional co-regulator, recently found to promote transcription factor E-B (TFEB) expression. Thus, polyQ-htt transcriptional dysregulation leads to impaired TFEB transactivation of its target genes, which encode the proteins and enzymes required for autophagosome assembly, autophagosome-lysosome fusion and lysosomaldegradative enzyme activity (D). Hence, polyQ-htt appears capable of undermining autophagy pathway function for two branches of autophagy (macroautophagy and chaperone-mediated autophagy), and can act through multiple mechanisms for macroautophagy inhibition.