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Molecular Pathogenesis in Huntington’s Disease

Abstract

Huntington’s disease (HD) is a severe autosomal dominant neurodegenerative disorder characterized by a combination of motor, cognitive, and psychiatric symptoms, atrophy of the basal ganglia and the cerebral cortex, and inevitably progressive course resulting in death 5–20 years after manifestation of its symptoms. HD is caused by expansion of CAG repeats in the HTT gene, which leads to pathological elongation of the polyglutamine tract within the respective protein-huntingtin. In this review, we present a modern view on molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. Main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as systemic failure of transcription, mitochondrial dysfunction and suppression of energy metabolism, abnormalities of cytoskeleton and axonal transport, microglial inflammation, decrease in synthesis of brain-derived neurotrophic factor, etc.

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Abbreviations

BDNF:

brain-derived neurotrophic factor

CNS:

central nervous system

HD:

Huntington’s disease

PGC-1α:

peroxisome proliferator-activated receptor γ coactivator 1α

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Correspondence to S. N. Illarioshkin.

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Original Russian Text © S. N. Illarioshkin, S. A. Klyushnikov, V. A. Vigont, Yu. A. Seliverstov, E. V. Kaznacheyeva, 2018, published in Biokhimiya, 2018, Vol. 83, No. 9, pp. 1299–1310.

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Illarioshkin, S.N., Klyushnikov, S.A., Vigont, V.A. et al. Molecular Pathogenesis in Huntington’s Disease. Biochemistry Moscow 83, 1030–1039 (2018). https://doi.org/10.1134/S0006297918090043

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Keywords

  • Huntington’s disease
  • molecular pathogenesis
  • polyglutamine expansion
  • proteolytic stress
  • transcription dysregulation
  • mitochondria