. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell. 2004 Oct 1;119(1):121-35. PubMed.

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  1. The excellent study by Spiegelman and colleagues shows that the absence of PGC-1 α, a coactivator of transcription factors including the PPAR family of nuclear receptors, leads to Huntington disease-like neurodegeneration in the mouse brain. As mentioned by the authors, a key implication of the study is that “in addition to its well established role in regulating mitochondrial gene expression, PGC-1α may have an important function in the control of neuronal gene expression and function.” The study thus suggests a PGC-1α-mediated link between mitochondrial activity and neurogenesis, and opens the possibility that modulation of PGC activity could be of therapeutic interest in neurodegenerative diseases.

    These are important ideas, and it is tempting to draw a connection to neurodegenerative diseases like AD wherein: 1) mitochondrial dysfunction could be a pathogenic factor, and 2) the therapeutic benefit of treatment with PPAR agonists is currently being examined in several clinical trials. It is too premature, however, to suggest a role of PGC-1α—or lack thereof—in AD. First, the areas altered in the PGC-1α-null mouse—striatum—and the symptom—hyperactivity—are not characteristic of AD. It should be noted, however, that the study explores the consequences of PGC deficiency in brain development but not in synaptic plasticity at an older age. Second, while stimulation with PPAR agonists is being considered for AD(see ARF related news story) the already very comprehensive study by Spiegelman et al. does not reveal whether the neurodegeneration resulting from PGC-1α depletion is related to PPARs. There is thus no basis to argue that activation of PGC-1α-mediated pathways may account for the benefits derived from PPAR treatment, although this is certainly an interesting possibility to explore.

    View all comments by Elena Galea