Huntingtin-associated protein 1

Huntingtin-associated protein 1 (HAP1) is a protein which in humans is encoded by the HAP1 gene.[1][2] 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.

huntingtin-associated protein 1 (neuroan 1)
Identifiers
SymbolHAP1
Alt. symbolsHAP2
NCBI gene9001
HGNC4812
OMIM600947
RefSeqNM_003949
UniProtP54257
Other data
LocusChr. 17 q21.2-21.3
Search for
StructuresSwiss-model
DomainsInterPro

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.[3]

Variants

Huntingtin-associated protein 1 has two subtypes; HAP1A and HAP1B.[4]

Function

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.[5] 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[6] 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. They also identified HAP1 in numerous areas of the cortex, including the anterior cingulate cortex and the limbic cortex.

The subcellular location of HAP1 closely resembles that of Htt. Gutekunst and colleagues[7] used immunogold labeling to identify subcellular localization of both HAP1 and muHtt, and identified a close similarity of the distribution of the two proteins. They did not find HAP1 labeling in protein aggregates in the cytoplasm and postulated that this indicated HAP1 in pre-aggregate related HD pathogenesis.

The role of HAP1 in HD pathogenesis may involve aberration of cell cycle processes, as high immunostaining of HAP1 during the cell cycle has been observed. It may have a part in spindle orientation, microtubule stabilization or chromosome movement. More importantly, HAP1 may also disrupt endocytosis, as it has been detected on vesicles involved in the early stages of this process. It is possible that the non-pathogenic activity of HAP1 is intracellular trafficking and that this is perturbed following its association with mHtt. HAP1 also interacts with proteins other than Htt and it is likely that their function is altered in HD pathogenesis. These include dynactin p150Glued, a cytoplasmic dynein accessory protein involved in retrograde transport of organelles, and kinesin-like protein which is another transport-mediation protein.

HAP1 also shows a similar CNS distribution pattern to that of neural nitric oxide synthase (nNos), especially in both of the pedunculopontine nuclei, the supraoptic nucleus, and the olfactory bulb. The possible significance of this interaction is that increased HAP1 interaction with muHtt may also increase nitric oxide (NO) thus facilitating neuronal damage.[8]

HAP1 also interacts with other factors involved in vesicular trafficking including GABAA receptor, Rho-GEF, and HGS.

References
  1. Li XJ, Li SH, Sharp AH, Nucifora FC, Schilling G, Lanahan A, Worley P, Snyder SH, Ross CA (November 1995). "A huntingtin-associated protein enriched in brain with implications for pathology". Nature. 378 (6555): 398–402. Bibcode:1995Natur.378..398L. doi:10.1038/378398a0. PMID 7477378. S2CID 4339298.
  2. Li SH, Hosseini SH, Gutekunst CA, Hersch SM, Ferrante RJ, Li XJ (July 1998). "A human HAP1 homologue. Cloning, expression, and interaction with huntingtin". J. Biol. Chem. 273 (30): 19220–7. doi:10.1074/jbc.273.30.19220. PMID 9668110.
  3. "Entrez Gene: HAP1 huntingtin-associated protein 1".
  4. Li SH, Li XJ (October 2004). "Huntingtin and its role in neuronal degeneration". Neuroscientist. 10 (5): 467–75. doi:10.1177/1073858404266777. PMID 15359012. S2CID 19491573.
  5. Martin EJ, Kim M, Velier J, Sapp E, Lee HS, Laforet G, Won L, Chase K, Bhide PG, Heller A, Aronin N, Difiglia M (January 1999). "Analysis of Huntingtin-associated protein 1 in mouse brain and immortalized striatal neurons". J. Comp. Neurol. 403 (4): 421–30. doi:10.1002/(SICI)1096-9861(19990125)403:4<421::AID-CNE1>3.0.CO;2-5. PMID 9888310. S2CID 20210908.
  6. Page KJ, Potter L, Aronni S, Everitt BJ, Dunnett SB (May 1998). "The expression of Huntingtin-associated protein (HAP1) mRNA in developing, adult and ageing rat CNS: implications for Huntington's disease neuropathology". Eur. J. Neurosci. 10 (5): 1835–45. doi:10.1046/j.1460-9568.1998.00185.x. PMID 9751154. S2CID 23547800.
  7. Gutekunst CA, Li SH, Yi H, Ferrante RJ, Li XJ, Hersch SM (October 1998). "The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human". J. Neurosci. 18 (19): 7674–86. doi:10.1523/JNEUROSCI.18-19-07674.1998. PMC 6793025. PMID 9742138.
  8. Li XJ, Sharp AH, Li SH, Dawson TM, Snyder SH, Ross CA (May 1996). "Huntingtin-associated protein (HAP1): discrete neuronal localizations in the brain resemble those of neuronal nitric oxide synthase". Proc. Natl. Acad. Sci. U.S.A. 93 (10): 4839–44. Bibcode:1996PNAS...93.4839L. doi:10.1073/pnas.93.10.4839. PMC 39366. PMID 8643490.

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