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

期刊

AGEING RESEARCH REVIEWS
卷 69, 期 -, 页码 -

出版社

ELSEVIER IRELAND LTD
DOI: 10.1016/j.arr.2021.101358

关键词

Peripheral tissues; Intertissue signaling; Ageing; Neurodegeneration; Huntington's disease

资金

  1. Ellison Medical Foundation
  2. Glenn Foundation for Medical Research
  3. American Federation for Aging Research
  4. Hartwell Foundation
  5. American Parkinson Disease Association
  6. National Institute on Aging of the NIH [R01AG055532, R56AG063806]
  7. ALSAC

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Huntington disease is a neurodegenerative disorder caused by a genetic mutation, affecting both the central nervous system and peripheral tissues. Systemic signaling from peripheral tissues can influence the progression of the disease in the brain, showcasing the interconnected nature of Huntington disease pathogenesis.
Huntington 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, HTTpolyQ 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 may impact HD. In summary, these studies indicate that HD is a systemic disease that is influenced by intertissue signaling and by the action of pathogenic HTT in peripheral tissues. We propose that treatment strategies for HD should include the amelioration of HD symptoms in peripheral tissues. Moreover, harnessing signaling between peripheral tissues and the brain may provide a means for reducing HD progression in the central nervous system.

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