DISEASE: Huntington disease
Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). The symptoms are choreiform, involuntary movements, personality changes and dementia. HD is caused by a CAG repeat expansion in the IT15 gene, which results in a long stretch of polyglutamine (polyQ) close to the amino-terminus of the HD protein huntingtin (Htt). Mutant Htt (mHtt) has effects both in the cytoplasm and in the nucleus. Full-length Htt is cleaved by proteases in the cytoplasm, leading to the formation of cytoplasmic and neuritic aggregates. mHtt also alters vesicular transport and recycling, causes cytosolic and mitochondrial Ca2+ overload, triggers endoplasmic reticulum stress through proteasomal dysfunction, and impairs autophagy function, increasing neuronal death susceptibility. N-terminal fragments containing the polyQ strech translocate to the nucleus where they impair transcription and induce neuronal death.
Human diseases [BR:
Nervous system diseases
H00059 Huntington disease
Human diseases in ICD-11 classification [BR:
08 Diseases of the nervous system
8A01 Choreiform disorders
H00059 Huntington disease
Mutation-caused aberrant Htt to retrograde axonal transport
Mutation-caused aberrant Htt to anterograde axonal transport
Mutation-caused aberrant Htt to REST-mediated transcriptional repression
Mutation-caused aberrant Htt to CREB-mediated transcription
Mutation-caused aberrant Htt to p53-mediated transcription
Mutation-caused aberrant Htt to extrinsic apoptotic pathway
Mutation-caused aberrant Htt to mGluR5-Ca2+ -apoptotic pathway
Mutation-caused aberrant Htt to VGCC-Ca2+ -apoptotic pathway
Mutation-caused aberrant Htt to transport of calcium
Mutation-caused aberrant Htt to electron transfer in Complex II
Mutation-caused aberrant Htt to electron transfer in Complex III
Mutation-caused aberrant Htt to TNF-JNK signaling pathway
Mutation-caused aberrant Htt to autophagy-vesicle nucleation
Mutation-caused aberrant Htt to 26S proteasome-mediated protein degradation
HTT; huntingtin (CAG repeat expansion) [HSA:
Disease class: polyglutamine disease
Affected region: caudate nucleus, globus pallidus, thalamus, hippocampus
Microscopic lesion: neuronal intranuclear inclusions
Imarisio S, Carmichael J, Korolchuk V, Chen CW, Saiki S, Rose C, Krishna G, Davies JE, Ttofi E, Underwood BR, Rubinsztein DC
Huntington's disease: from pathology and genetics to potential therapies.
Biochem J 412:191-209 (2008)
Spires TL, Hannan AJ
Molecular mechanisms mediating pathological plasticity in Huntington's disease and Alzheimer's disease.
J Neurochem 100:874-82 (2007)
Gusella JF, Macdonald ME
Huntington's disease: seeing the pathogenic process through a genetic lens.
Trends Biochem Sci 31:533-40 (2006)
Gardian G, Vecsei L.
Huntington's disease: pathomechanism and therapeutic perspectives.
J Neural Transm 111:1485-94 (2004)
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