Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1α in Huntington's disease neurodegeneration

Abstract

Huntington's disease (HD) is a fatal, dominantly inherited disorder caused by polyglutamine repeat expansion in the huntingtin (htt) gene. Here, we observe that HD mice develop hypothermia associated with impaired activation of brown adipose tissue (BAT). Although sympathetic stimulation of PPARgamma coactivator 1alpha (PGC-1alpha) was intact in BAT of HD mice, uncoupling protein 1 (UCP-1) induction was blunted. In cultured cells, expression of mutant htt suppressed UCP-1 promoter activity; this was reversed by PGC-1alpha expression. HD mice showed reduced food intake and increased energy expenditure, with dysfunctional BAT mitochondria. PGC-1alpha is a known regulator of mitochondrial function; here, we document reduced expression of PGC-1alpha target genes in HD patient and mouse striatum. Mitochondria of HD mouse brain show reduced oxygen consumption rates. Finally, HD striatal neurons expressing exogenous PGC-1alpha were resistant to 3-nitropropionic acid treatment. Altered PGC-1alpha function may thus link transcription dysregulation and mitochondrial dysfunction in HD.

Calcium Homeostasis and Mitochondrial Dysfunction in Striatal Neurons of Huntington Disease

“…As a result, the transcription of ROS-scavenging enzymes is down-regulated, and the concentration of ROS in the neurons increases. These important observations were reinforced by the finding that striatal neurons from HD knock-in mice were resistant to 3-NPA when expressing exogenous PGC-1␣ (22).…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…Whether the brain-specific isoforms have functional activation domains remains to be determined. Interestingly, the newly identified promoter that mediates the transcription of these brain PGC-1α isoforms is located in a genomic region associated with age of onset of Huntington's disease [41], a disease that has been linked to altered PGC-1α function [42][43][44]. …”

HIF Prolyl Hydroxylase Inhibitors Prevent Neuronal Death Induced by Mitochondrial Toxins: Therapeutic Implications for Huntington's Disease and Alzheimer's Disease

“…First, HD is attributable to an expanded glutamine repeat stretch in the protein huntingtin (mhtt). Among its many cellular manifestations, mhtt leads to transcriptional repression of many genes, including those controlling adaptation to low mitochondrial energy charge such as PPARg coactivator 1a (PGC-1a) (7,8,35). Indeed, recent studies have shown that germline deletion of PGC-1a leads to striatal degeneration similar in localization and behavioral manifestations to HD (17); by contrast, PGC-1a overexpression via lentiviral delivery in vivo prevents striatal degeneration attributable to transgenic expression of mhtt (8).…”