Huntingtin-associated protein 1

Variants

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

Function

HAP1 preferentially interacts with 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. 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 used immunogold labeling to identify subcellular localization of both HAP1 and , 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 . 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.

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

References

References

1. (November 1995). "A huntingtin-associated protein enriched in brain with implications for pathology". Nature.
2. (July 1998). "A human HAP1 homologue. Cloning, expression, and interaction with huntingtin". J. Biol. Chem..
3. "Entrez Gene: HAP1 huntingtin-associated protein 1".
4. (October 2004). "Huntingtin and its role in neuronal degeneration". Neuroscientist.
5. (January 1999). "Analysis of Huntingtin-associated protein 1 in mouse brain and immortalized striatal neurons". J. Comp. Neurol..
6. (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..
7. (October 1998). "The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human". J. Neurosci..
8. (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..