PGC-1α’s Emerging Roles—Neuroprotection and Neurodegeneration
Four recent articles focus on the importance of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), a transcriptional regulator involved in mitochondrial biogenesis, tissue differentiation, and energy homeostasis. One paper illustrates the protein’s neuroprotective role while three implicate its loss of function as a cause of neurodegeneration. St-Pierre and colleagues (1) show that PGC-1α transcription is upregulated in response to reactive oxygen species (ROS). Consequently, this increase in PGC-1α leads to higher expression of genes that are involved in suppressing ROS toxicity. In addition, their study showed that ablation of PGC-1α increased susceptibility to neuronal insults induced by ROS-generating toxins and depolarizing agents. In contrast, PGC-1α overexpression protected against ROS insults, further cementing the important role this protein plays in neuroprotection.

The other studies present evidence that decreased expression and/or loss of function of PGC-1α underlie...  Read more

PGC-1α’s Emerging Roles—Neuroprotection and Neurodegeneration
Four recent articles focus on the importance of the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α), a transcriptional regulator involved in mitochondrial biogenesis, tissue differentiation, and energy homeostasis. One paper illustrates the protein’s neuroprotective role while three implicate its loss of function as a cause of neurodegeneration. St-Pierre and colleagues (1) show that PGC-1α transcription is upregulated in response to reactive oxygen species (ROS). Consequently, this increase in PGC-1α leads to higher expression of genes that are involved in suppressing ROS toxicity. In addition, their study showed that ablation of PGC-1α increased susceptibility to neuronal insults induced by ROS-generating toxins and depolarizing agents. In contrast, PGC-1α overexpression protected against ROS insults, further cementing the important role this protein plays in neuroprotection.

The other studies present evidence that decreased expression and/or loss of function of PGC-1α underlie the neurodegenerative and metabolic deficits in Huntington disease (HD) and Leigh syndrome French Canadian variant (LSFC). In the Cooper paper(2), the authors report that loss of the 130 kDa leucine-rich protein (LRP130), an adaptor protein for PGC-1α, results in transcriptional dysregulation of specific PGC-1α targets. In Cui et al. (3), transcriptional repression of PGC-1α by the polyglutamine-expanded huntingtin (htt) protein causes mitochondrial deficits and neurodegeneration. In a study we published recently in Cell Metabolism (4), we implicated mutant htt-mediated transcriptional dysregulation of PGC-1α targets as the underlying cause of the thermoregulatory, neurodegenerative and metabolic dysfunctions in an HD mouse model. Furthermore, we showed that PGC-1α target genes are downregulated in the caudate of human HD patients compared to normal controls as additional evidence of the importance of PGC-1α in HD pathogenesis.

These papers present the importance of PGC-1α in maintaining neuronal integrity, either when faced with exogenous environmental insults or with toxic mutant proteins. Collectively, these reports point to a key player that can be viewed as an attractive drug target for the treatment of HD or perhaps other neurodegenerative disorders. A pharmacological agent that can increase neuronal expression or transcriptional activity of PGC-1α may be able to ameliorate the toxic effects of mutant proteins or perhaps reverse the accumulated oxidative damage associated with the aging process.

References:
1. St-Pierre J, Drori S, Uldry M, Silvaggi JM, Rhee J, Jager S, Handschin C, Zheng K, Lin J, Yang W, Simon DK, Bachoo R, Spiegelman BM. Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell. 2006 Oct 20;127(2):397-408. Abstract

2. Cooper MP, Qu L, Rohas LM, Lin J, Yang W, Erdjument-Bromage H, Tempst P, Spiegelman BM. Defects in energy homeostasis in Leigh syndrome French Canadian variant through PGC-1alpha/LRP130 complex. Genes Dev. 2006 Nov 1;20(21):2996-3009. Epub 2006 Oct 18. Abstract

3. Cui L, Jeong H, Borovecki F, Parkhurst CN, Tanese N, Krainc D. Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell. 2006 Oct 6;127(1):59-69. Abstract

4. Weydt P, Pineda VV, Torrence AE, Libby RT, Satterfield TF, Lazarowski ER, Gilbert ML, Morton GJ, Bammler TK, Strand AD, Cui L, Beyer RP, Easley CN, Smith AC, Krainc D, Luquet S, Sweet IR, Schwartz MW, La Spada AR. Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab. 2006 Nov;4(5):349-62. Epub 2006 Oct 19. Abstract

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