NRF1 and Huntington disease: HD is the most frequent autosomal dominant neurodegenerative disorder resulting from an abnormally expanded CAG repeat expansion in the huntingtin (HTT) gene, which confers a predominant toxic gain of function in the mutant HTT protein.469 Remarkably, PGC-1α is downregulated in patients with HD and genetic repression of PGC-1α by mutant HTT increases striatal neurodegeneration and motor coordination in mice.470,471 Meanwhile, its upstream modulators, including TORCs and downstream transcription factors, such as NRF-1 and TFAM, are also downregulated.472,473