title: PPARGC1A/PGC-1α, TFEB and enhanced proteostasis in Huntington disease: defining regulatory linkages between energy production and protein-organelle quality control.
abstract: Huntington disease (HD) results from CAG repeats that encode expanded polyglutamine tracts in the HTT/huntingtin protein. HD belongs to a large category of inherited and sporadic neurodegenerative disorders in which production of a misfolded protein initiates the pathogenic cascade. Previous studies have shown that misfolded proteins become resistant to cellular protein turnover pathways by eluding and disabling the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway. Based upon earlier work implicating impaired PPARGC1A function in HD, we derived inducible PPARGC1A mice and crossed them with HD mice. We found that PPARGC1A overexpression can rescue HD neurological phenotypes and neurodegeneration. An unexpected outcome of the rescue was the virtual elimination of huntingtin aggregates, and we found that PPARGC1A-mediated aggregate elimination required the autophagy pathway. Moreover, we observed decreased expression of transcription factor EB (TFEB), a master regulator of the autophagy-lysosome pathway, in HD cells and mice, and documented PPARGC1A co-activation of TFEB in these model systems, noting that PPARGC1A is upstream of TFEB in promoting proteostasis. These findings underscore the importance of bioenergetics and autophagy in neurodegeneration, and indicate that PPARGC1A promotes mitochondrial quality control to support high-energy production states in cells, such as neurons. As impaired energy production and altered protein-organelle quality control appear inextricably linked in disorders such as HD, Parkinson disease, and Alzheimer disease, efforts directed at enhancing PPARGC1A and TFEB action may represent viable strategies for therapy development in neurodegeneration.
authors.affiliation: Departments of Pediatrics, Cellular and Molecular Medicine, and Neurosciences, Division of Biological Sciences, Institute for Genomic Medicine, and the Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, USA. alaspada@ucsd.edu
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D004734:Energy Metabolism; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D015388:Organelles / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000378:metabolism* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1