Transcriptional Dysregulation in Huntington's Disease: The Role in Pathogenesis and Potency for Pharmacological Targeting

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the gene that encodes a critical cell regulatory protein, huntingtin (Htt). The expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats causes improper folding of functional proteins and is an initial trigger of pathological changes in the brain. Recent research has indicated that the functional dysregulation of many transcription factors underlies the neurodegenerative processes that accompany HD. These disturbances are caused not only by the loss of wild-type Htt (WT Htt) function but also by the occurrence of abnormalities that result from the action of mutant Htt (mHtt). In this review, we aim to describe the role of transcription factors that are currently thought to be strongly associated with HD pathogenesis, namely, RE1-silencing transcription factor, also known as neuron-restrictive silencer factor (REST/NRSF), forkhead box proteins (FOXPs), peroxisome proliferator-activated receptor gamma coactivator-1a (PGC1 alpha), heat shock transcription factor 1 (HSF1), and nuclear factor K light-chain-enhancer of activated B cells (NFKB). We also take into account the role of these factors in the phenotype of HD as well as potential pharmacological interventions targeting the analyzed proteins. Furthermore, we considered whether molecular manipulation resulting in changes in transcription factor function may have clinical potency for treating HD.

Automated summary

Huntington's disease is a genetic neurodegenerative disorder caused by a mutation in the Htt gene. Dysfunction of multiple transcription factors is implicated in the pathological changes associated with HD. Investigating the role of these transcription factors in the development of HD may lead to potential therapeutic interventions.