Molecular Pathogenesis in Huntington’s Disease

• Published in: Biochemistry (Moscow) Vol. 83; no. 9; pp. 1030 - 1039
• Main Authors: Illarioshkin, S. N., Klyushnikov, S. A., Vigont, V. A., Seliverstov, Yu. A., Kaznacheyeva, E. V.
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 01.09.2018; Springer; Springer Nature B.V
• Subjects: Atrophy; Axonal transport; Axonal Transport - physiology; Basal ganglia; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Brain-derived neurotrophic factor; Cerebral cortex; Cognitive ability; CREB-Binding Protein - metabolism; Cytoskeleton; Cytoskeleton - metabolism; Development and progression; Energy metabolism; Energy Metabolism - physiology; Genetic aspects; Hereditary diseases; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington's disease; Huntingtons disease; Life Sciences; Microbiology; Mitochondria; Mitochondria - metabolism; Molecular biology; Neurodegeneration; Neurodegenerative diseases; Peptides - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Polyglutamine diseases; Proteolysis; Review; Transcription; Trinucleotide repeat diseases; Trinucleotide repeats; transcription dysregulation; Huntington’s disease; proteolytic stress; polyglutamine expansion; mitochondria; molecular pathogenesis
• ISSN: 0006-2979; 1608-3040
• DOI: 10.1134/S0006297918090043

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.