Abstract
Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) in the pathophysiology of Huntington Disease (HD). Adult PGC-1α −/− mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1α have been observed in striatum and muscle of HD patients as well as in animal models of the disease. However, it is unknown whether decreased expression of PGC-1α alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1α −/− mice exhibit severe rotarod deficits, decreased rearing behavior, and increased occurrence of tremor in addition to the previously described hindlimb clasping. Motor impairment and striatal vacuolation are apparent in PGC-1α −/− mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1α −/− mice can be completely recapitulated by conditional nervous system deletion of PGC-1α, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1α −/− striatal neuron populations and comparison to striatal neuron profiles of R6/2 HD mice revealed that PGC-1α deficiency alone is not sufficient to cause the transcriptional changes observed in this HD mouse model. In contrast to R6/2 HD mice, PGC-1α −/− mice show increases in the expression of medium spiny neuron (MSN) markers with age, suggesting that the observed behavioral and structural abnormalities are not primarily due to MSN loss, the defining pathological feature of HD. These results indicate that PGC-1α is required for the proper development of motor circuitry and transcriptional homeostasis in MSNs and that developmental disruption of PGC-1α leads to long-term alterations in motor functioning.
Highlights
Huntington disease (HD) is a debilitating autosomal dominant disorder involving progressive deterioration of motor and psychiatric functioning over a period of years, leading to death
A hallmark in the pathology of HD is severe atrophy of the striatum mediated by a preferential loss of the medium spiny projection neurons (MSNs) in this region [2], other brain regions and cell types are affected to a lesser extent by the presence of mutant huntingtin [3,4]
MHtt aggregates to form cytosolic and intranuclear inclusions. It is currently unknown if loss of function of native huntingtin protein and/or gain of function of the mutant protein results in the cell death observed in HD
Summary
Huntington disease (HD) is a debilitating autosomal dominant disorder involving progressive deterioration of motor and psychiatric functioning over a period of years, leading to death. A hallmark in the pathology of HD is severe atrophy of the striatum mediated by a preferential loss of the medium spiny projection neurons (MSNs) in this region [2], other brain regions and cell types are affected to a lesser extent by the presence of mutant huntingtin (mHtt) [3,4]. MHtt aggregates to form cytosolic and intranuclear inclusions. It is currently unknown if loss of function of native huntingtin protein and/or gain of function of the mutant protein results in the cell death observed in HD. There is a large body of evidence to support the involvement of mitochondrial dysfunction [5,6] and transcriptional dysregulation [7] in HD pathology. The transcriptional coactivator peroxisome proliferator activated receptor c coactivator 1a (PPARGC1A or PGC-1a) has been proposed to be a link between these features [8,9]
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