HAP1

Description

The HAP1 (huntingtin associated protein 1) is a protein-coding gene located on chromosome 17.

Huntingtin-associated protein 1 (HAP1) is a protein which in humans is encoded by the HAP1 gene. This protein was found to bind to the mutant huntingtin protein (mHtt) in proportion to the number of glutamines present in the glutamine repeat region. Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with huntingtin, with two cytoskeletal proteins (dynactin and pericentriolar autoantigen protein 1), and with a hepatocyte growth factor-regulated tyrosine kinase substrate (HGS). The interactions with cytoskeletal proteins and a kinase substrate suggest a role for this protein in vesicular trafficking or organelle transport. Huntingtin-associated protein 1 has two subtypes; HAP1A and HAP1B. HAP1 preferentially interacts with muHtt in a polyQ dependent manner. Its localization and possible interacting partners (other than Htt) have since been characterised, thus elucidating a possible role for this protein in HD pathogenesis. Martin et al. showed that HAP1 is localized in mitotic spindle of dividing striatal cells, and associated endosomes, microtubules and vesicles in the basal forebrain and striatial neurons – where HAP1B is preferentially expressed. Furthermore, Page and colleagues identified HAP1 mRNA in the following forebrain limbic nuclei: the amygdala, nucleus accumbens, dentate gyrus, septal nuclei, bed nucleus of the stria terminalis, and hypothalamus.

HAP1, also known as Neuroan1, is a neuronal protein that interacts with HTT/huntingtin, with this interaction being strengthened by an expanded polyglutamine repeat within HTT. Both HTT and HAP1 are involved in intracellular trafficking, and HAP1 is thought to connect HTT to motor proteins and/or transport cargos. HAP1 plays a role in vesicular transport within neurons and axons, moving cargo from early endosomes to late endocytic compartments and promoting neurite outgrowth. This vesicular transport function, mediated by microtubule-dependent transporters, can be impaired by association with mutant HTT. HAP1 is involved in the axonal transport of BDNF and its activity-dependent secretion, a process that likely involves HTT, DCTN1, and a complex with SORT1. HAP1 also contributes to APP trafficking, facilitating its anterograde transport and membrane insertion, potentially reducing its processing into amyloid beta. HAP1 is crucial for delivering gamma-aminobutyric acid (GABA(A)) receptors to synapses, a function dependent on the kinesin motor protein KIF5 and disrupted by HTT with an expanded polyglutamine repeat. HAP1 regulates autophagosome motility by promoting efficient retrograde axonal transport. It also seems to regulate membrane receptor recycling and degradation, and associated signal transduction, involving GABA(A) receptors, tyrosine kinase receptors, EGFR, IP3 receptor, and androgen receptor. HAP1 has been suggested to be involved in controlling feeding behavior (via hypothalamic GABA(A) receptors), cerebellar and brainstem development (via AHI1 and NTRK1/TrkA), postnatal neurogenesis (via hypothalamic NTRK2/TrkB), and ITPR1/InsP3R1-mediated Ca(2+) release (via HTT and potentially the effect of mutant HTT). In conjunction with DCTN1/dynactin p150-glued and HTT/huntingtin, HAP1 is involved in cytoplasmic retention of REST in neurons. HAP1 may play a role in ciliogenesis and regulates exocytosis. HAP1 is involved in the formation of cytoplasmic inclusion bodies (STBs). In cases of anomalous TBP expression, HAP1 can sequester a subset of TBP into STBs, a process enhanced by an expanded polyglutamine repeat within TBP. HAP1-containing STBs are proposed to provide protection against neurodegeneration in Huntington's disease (HD) and spinocerebellar ataxia 17 (SCA17).

HAP1 is also known as HAP2, HIP5, HLP, hHLP1.

Associated Diseases

WES Whole Exome Sequencing