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

[ Vol. 28 , Issue. 14 ]

Author(s):

Aleksandra Pogoda, Natalia Chmielewska*, Piotr Maciejak and Janusz Szyndler   Pages 2783 - 2806 ( 24 )

Abstract:


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 (PGC1α), heat shock transcription factor 1 (HSF1), and nuclear factor κ light-chain-enhancer of activated B cells (NF- κB). 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.

Keywords:

Huntington's Disease, transcription factors, transcriptional dysregulation, REST/NRSF, FOXPs, PGC1α, HSF1, NF-κB.

Affiliation:

Faculty of Medicine, Medical University of Warsaw, Zwirki i Wigury Street 61, 02-097 Warsaw, Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Department of Neurochemistry, Institute of Psychiatry and Neurology, Sobieskiego Street 9, 02-957 Warsaw, Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology CePT, Medical University of Warsaw, Banacha Street 1B, 02-097 Warsaw



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