Gene-environment interactions, neuronal dysfunction and pathological plasticity in Huntington's disease.
Huntington's disease (HD) is a fatal autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. The dynamic mutation that causes the disease is common to numerous other brain disorders, which may share similar pathogenic mechanisms. Much progress has been made in the past decade in understanding how a trinucleotide (CAG) repeat expansion, encoding an expanded polyglutamine tract in the huntingtin protein, induces dysfunction at molecular and cellular levels. The present review integrates various lines of experimental evidence in an attempt to move towards a unifying mechanistic framework, which may explain the pathogenesis of HD, from molecular through to neuronal network and behavioural levels. Recent evidence, using transgenic mouse models, also suggests that environmental factors can modify the onset and progression of HD. The effects of specific environmental manipulations are discussed in the context of gene-environment interactions and experience-dependent plasticity in the healthy and diseased brain, particularly the cerebral cortex.
van Dellen
Anton
A
University Laboratory of Physiology, University of Oxford, Oxford, UK.
Grote
Helen E
HE
Hannan
Anthony J
AJ
D000818:Animals; D001519:Behavior / Q000502:physiology; D001522:Behavior, Animal; D016923:Cell Death; D006801:Humans; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D021382:Protein Sorting Signals / Q000235:genetics
D009419:Nerve Tissue Proteins; D010455:Peptides; D021382:Protein Sorting Signals; C097188:polyglutamine