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Description

Huntingtin (UniProt: P42858, also known as Huntington disease protein, HD protein) is encoded by the HTT (also known as HD, IT15) gene (Gene ID: 3064) in human. This protein is found in the perinuclear region along with microtubules, and in the centrosomal region along with g-tubulin. It is expressed in the brain and is mainly found in the cerebellar cortex, the neocortex, the striatum, and the hippocampal formation. It plays a role in microtubule-mediated transport or vesicle function and shown to be necessary for neuronal survival. It is involved in synaptic vesicle trafficking, and microtubule binding. It contains a nuclear export signal (aa 2395-2404) and 5 HEAT (Huntington, Elongation Factor 3, PR65/A, TOR) domains. It can undergo cleavage by caspases downstream of the polyglutamine stretch and the resulting N-terminal fragments displays cytotoxicity and provokes apoptosis. In response to DNA damage, it undergoes phosphorylation at Serine 1179 and 1199 by CDK5 that is shown to protect neurons against polyglutamine expansion as well as DNA damage mediated toxicity. The N-terminal fragments of mutant huntingtin (mHTT) misfold and assemble into oligomers that ultimately bundle into insoluble fibrils. Misfolding and self-aggregation of specific proteins is commonly observed in well-known neurodegenerative diseases, including Huntington s disease (HD), Alzheimer s disease (AD), Parkinson s disease (PD), and amyotrophic lateral sclerosis (AML). Abnormal polyglutamine (polyQ) repeat sequence or stretch result in protein misfolding and neurodegeneration.