Epigenetics of Huntington’s Disease

Abstract

Huntington's disease (HD) is a genetic, fatal autosomal dominant neurodegenerative disorder typically occurring in midlife with symptoms ranging from chorea, to dementia, to personality disturbances (Philos Trans R Soc Lond Ser B Biol Sci 354:957-961, 1999). HD is inherited in a dominant fashion, and the underlying mutation in all cases is a CAG trinucleotide repeat expansion within exon 1 of the HD gene (Cell 72:971-983, 1993). The expanded CAG repeat, translated into a lengthened glutamine tract at the amino terminus of the huntingtin protein, affects its structural properties and functional activities. The effects are pleiotropic, as huntingtin is broadly expressed in different cellular compartments (i.e., cytosol, nucleus, mitochondria) as well as in all cell types of the body at all developmental stages, such that HD pathogenesis likely starts at conception and is a lifelong process (Front Neurosci 9:509, 2015). The rate-limiting mechanism(s) of neurodegeneration in HD still remains elusive: many different processes are commonly disrupted in HD cell lines and animal models, as well as in HD patient cells (Eur J Neurosci 27:2803-2820, 2008); however, epigenetic-chromatin deregulation, as determined by the analysis of DNA methylation, histone modifications, and noncoding RNAs, has now become a prevailing feature. Thus, the overarching goal of this chapter is to discuss the current status of the literature, reviewing how an aberrant epigenetic landscape can contribute to altered gene expression and neuronal dysfunction in HD.

Lifestyle Modifications and Nutritional Interventions in Aging-Associated Cognitive Decline and Alzheimer’s Disease

“…Besides the nuclear DNA, there is growing evidence that the mitochondrial DNA (mtDNA) could be controlled by epigenetic mechanisms (Hroudová et al, 2014;Blanch et al, 2016;Stoccoro et al, 2017). Several studies have demonstrated the impact of epigenetic modifications on the pathogenesis of neurodegenerative diseases (Urdinguio et al, 2009;Gruber, 2011;Gangisetty and Murugan, 2016;Bassi et al, 2017;Smith and Lunnon, 2017;Berson et al, 2018;Gangisetty et al, 2018;Lardenoije et al, 2018;Lascano et al, 2018;Qazi et al, 2018;Stoccoro and Coppedè, 2018). There is a growing body of evidence suggesting that epigenetic mechanisms mediate the risk for AD.…”

How Do Post-Translational Modifications Influence the Pathomechanistic Landscape of Huntington’s Disease? A Comprehensive Review

“…Transcriptional dysregulation is an early problem in HD and includes alterations in both histone modifications and the function of gene expression regulators. These complications have been extensively researched, and the key findings are summarized by several review articles [56,251,252]. Wild-type HTT interacts with several transcription factors (CREB, SP1, NF-κB, NeuroD, p53, UBF), transcriptional activators and repressors (TAFII130, CA150, NCOR, REST/NRSF, PGC-1α), and nuclear receptors (LXRα, PPARγ, VDR, TRα1) (reviewed in [251,252]).…”

The Dynamic Partnership of Polycomb and Trithorax in Brain Development and Diseases

“…Recently, the importance of the delicate balance between PcG and TrxG proteins throughout brain development-particularly embryonic and adult neurogenesis, aging, neuroprotection and neurodegeneration-is being recognized [4][5][6]. The aberrant expression of either PcG or TrxG proteins is beginning to be associated with neurodegenerative disease, such as Alzheimer's, Huntington's and Parkinson's disease [7][8][9]. The current challenge lies in determining the extent to which PcG and TrxG proteins play in the development and progression of these diseases, and if unique complexes exist that could act as early detection biomarkers.…”