| First Author | Lucas EK | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 8 | Pages | e42878 |
| PubMed ID | 22916173 | Mgi Jnum | J:190053 |
| Mgi Id | MGI:5447889 | Doi | 10.1371/journal.pone.0042878 |
| Citation | Lucas EK, et al. (2012) Developmental alterations in motor coordination and medium spiny neuron markers in mice lacking pgc-1alpha. PLoS One 7(8):e42878 |
| abstractText | Accumulating evidence implicates the transcriptional coactivator peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC-1alpha) in the pathophysiology of Huntington Disease (HD). Adult PGC-1alpha (-/-) mice exhibit striatal neurodegeneration, and reductions in the expression of PGC-1alpha 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-1alpha alone is sufficient to lead to the motor phenotype and striatal pathology characteristic of HD. For the first time, we show that young PGC-1alpha (-/-) 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-1alpha (-/-) mice by four weeks of age and do not improve or decline by twelve weeks of age. The behavioral and pathological phenotype of PGC-1alpha (-/-) mice can be completely recapitulated by conditional nervous system deletion of PGC-1alpha, indicating that peripheral effects are not responsible for the observed abnormalities. Evaluation of the transcriptional profile of PGC-1alpha (-/-) striatal neuron populations and comparison to striatal neuron profiles of R6/2 HD mice revealed that PGC-1alpha deficiency alone is not sufficient to cause the transcriptional changes observed in this HD mouse model. In contrast to R6/2 HD mice, PGC-1alpha (-/-) 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-1alpha is required for the proper development of motor circuitry and transcriptional homeostasis in MSNs and that developmental disruption of PGC-1alpha leads to long-term alterations in motor functioning. |
