Huntington disease update: new insights into the role of repeat instability in disease pathogenesis

Abstract

The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.

Protective Effect of Fustin against Huntington’s Disease in 3-Nitropropionic Treated Rats via Downregulation of Oxidative Stress and Alteration in Neurotransmitters and Brain-Derived Neurotrophic Factor Activity

“…The previous line of research also demonstrated that the HD gene is located on chromosomal 4p16 and expresses huntingtin a 348 kDa glycoprotein that is abundantly distributed throughout synapses [ 4 ]. Excitotoxicity, energy deprivation, oxidative damage, inflammatory response, and protein expression are among the mechanisms through which neurodegeneration proceeds in HD [ 5 ].…”

The Role of Hydrogen Sulfide (H2S) in Epigenetic Regulation of Neurodegenerative Diseases: A Systematic Review

“…In Huntington’s disease (HD), accumulating mutant huntingtin protein with an expanded polyglutamine repeat is critical in the disease process [ 105 ]. H 2 S has been shown to influence the aggregation and toxicity of mutant huntingtin, contributing to the degeneration of neurons in the striatum and other brain regions affected in HD.…”

The flavonoid luteolin reduces mutant huntingtin aggregation and cytotoxicity in huntingtin-mutated neuroblastoma cells

“…Huntington's disease (HD) is an inherited progressive neurodegenerative disorder belonging to the polyglutamine disorders ( McColgan and Tabrizi, 2018 ). Polyglutamine disorders share adult onset of symptoms, which include chorea, general motor impairment, psychiatric disorders, and cognitive decline ( Arning and Nguyen, 2021 ). The disease usually begins in midlife, with progressive neurodegeneration leading to death within ten years of onset ( Niemann and Jankovic, 2019 ).…”