Systemic manifestation and contribution of peripheral tissues to Huntington's disease pathogenesis

Ageing Res Rev. 2021 May 9;69:101358. doi: 10.1016/j.arr.2021.101358. Online ahead of print.ABSTRACTHuntington disease (HD) is an autosomal dominant neurodegenerative disease that is caused by expansion of cytosine/adenosine/guanine repeats in the huntingtin (HTT) gene, which leads to a toxic, aggregation-prone, mutant HTT-polyQ protein. Beyond the well-established mechanisms of HD progression in the central nervous system, growing evidence indicates that also peripheral tissues are affected in HD and that systemic signaling originating from peripheral tissues can influence the progression of HD in the brain. Herein, we review the systemic manifestation of HD in peripheral tissues, and the impact of systemic signaling on HD pathogenesis. Mutant HTT induces a body wasting syndrome (cachexia) primarily via its activity in skeletal muscle, bone, adipose tissue, and heart. Additional whole-organism effects induced by mutant HTT include decline in systemic metabolic homeostasis, which stems from derangement of pancreas, liver, gut, hypothalamic-pituitary-adrenal axis, and circadian functions. In addition to spreading via the bloodstream and a leaky blood brain barrier, HTT-polyQ may travel long distance via its uptake by neurons and its axonal transport from the peripheral to the central nervous system. Lastly, signaling factors that are produced and/or secreted in response to therapeutic interventions such as exercise or in response to mutant HTT activity in peripheral tissues ma...
Source: Ageing Research Reviews - Category: Genetics & Stem Cells Authors: Source Type: research