We investigated the role of PPAR gamma coactivator 1alpha (PGC-1alpha) in muscle dysfunction in Huntington's disease (HD). We observed reduced PGC-1alpha and target genes expression in muscle of HD transgenic mice. We produced chronic energy deprivation in HD mice by administering the catabolic stressor beta-guanidinopropionic acid (GPA), a creatine analogue that reduces ATP levels, activates AMP-activated protein kinase (AMPK), which in turn activates PGC-1alpha. Treatment with GPA resulted in increased expression of AMPK, PGC-1alpha target genes, genes for oxidative phosphorylation, electron transport chain and mitochondrial biogenesis, increased oxidative muscle fibers, numbers of mitochondria and motor performance in wild-type, but not in HD mice. In muscle biopsies from HD patients, there was decreased PGC-1alpha, PGC-1beta and oxidative fibers. Oxygen consumption, PGC-1alpha, NRF1 and response to GPA were significantly reduced in myoblasts from HD patients. Knockdown of mutant huntingtin resulted in increased PGC-1alpha expression in HD myoblast. Lastly, adenoviral-mediated delivery of PGC-1alpha resulted increased expression of PGC-1alpha and markers for oxidative muscle fibers and reversal of blunted response for GPA in HD mice. These findings show that impaired function of PGC-1alpha plays a critical role in muscle dysfunction in HD, and that treatment with agents to enhance PGC-1alpha function could exert therapeutic benefits. Furthermore, muscle may provide a readily accessible tissue in which to monitor therapeutic interventions.

Huntington disease (HD) is a progressive neurodegenerative monogenic disorder caused by expansion of a polyglutamine stretch in the huntingtin (Htt) protein. Mutant huntingtin triggers neural dysfunction and death, mainly in the corpus striatum and cerebral cortex, resulting in pathognomonic motor symptoms, as well as cognitive and psychiatric decline. Currently, there is no effective treatment for HD. We report that intraventricular infusion of ganglioside GM1 induces phosphorylation of mutant huntingtin at specific serine amino acid residues that attenuate huntingtin toxicity, and restores normal motor function in already symptomatic HD mice. Thus, our studies have identified a potential therapy for HD that targets a posttranslational modification of mutant huntingtin with critical effects on disease pathogenesis.H untington disease (HD) is an inherited neurodegenerative monogenic disorder caused by the expansion of a polyglutamine stretch beyond 36 residues in the amino-terminal domain of huntingtin (Htt), a protein expressed in most tissues and cells. The mutation causes huntingtin to acquire toxic conformation/s and to affect neuronal function and viability. Medium-sized spiny neurons in the corpus striatum are most affected, but neurodegeneration also occurs in the cerebral cortex and, to a minor extent, in other brain areas, resulting in motor and psychiatric symptoms, as well as cognitive decline.The cellular and molecular mechanisms underlying HD pathogenesis are complex. Both loss and gain of function of mutant huntingtin contribute to cause a wide array of neuronal dysfunctions affecting cell signaling, gene transcription, axonal transport, cell and mitochondrial metabolism as well as neurotransmission (1).In recent years, a breakthrough in HD research has been the discovery that posttranslational modifications of mutant Htt are crucial modulators of mutant Htt toxicity (2-4). Phosphorylation at various serine residues prevents cleavage of mutant huntingtin into more toxic fragments, decreases neural cell death in vitro (5-10), and/or restores Htt functions that are compromised by the mutation (8, 11). The most dramatic effects have been described for huntingtin phosphorylation at serine 13 and serine 16. These two amino acid residues are part of the highly conserved amino-terminal "N17" domain of huntingtin, a domain that regulates huntingtin intracellular localization and association to cellular membranes (12, 13), as well as kinetics of mutant huntingtin aggregation (14,15). Phosphomimetic mutations of serine 13 and serine 16 by aspartic or glutamic acid substitution (S13D and S16D or S13E and S16E) decrease the toxicity of mutant huntingtin fragments in vitro (10, 16). In line with these studies, expression of a phosphomimetic (S13D and S16D) mutant form of expanded full-length huntingtin in a BACHD transgenic mouse model was shown to result in a normal phenotype, with no detectable signs of HD pathology by 12 mo (17).These findings suggest that pharmacological interventions that modulate cell sig...

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