Disease relevance of Hap1

• Postnatally, Hap1(-/-) pups show decreased feeding behavior that ultimately leads to malnutrition, dehydration and premature death [1].
• We have mapped its murine homolog, Hap1, to mouse Chr 11 (band D), which shares extensive synteny with human Chr 17 including the region 17q21-q22, where the gene for 'frontotemporal dementia and parkinsonism linked to chromosome 17' has bee mapped [2].
• Decreasing the expression of mouse hypothalamic Hap1 by siRNA reduces the level and activity of hypothalamic GABA(A) receptors and causes a decrease in food intake and body weight [3].
• We have recently shown that HAP-1 maps to a region of the genome which has been implicated in a variety of neurological conditions, including progressive supranuclear palsy (PSP), a late-onset atypical parkinsonian disorder [4].
• Anticancer activity of bacteriophage T4 and its mutant HAP1 in mouse experimental tumour models [5].

Psychiatry related information on Hap1

• In contrast, little expression was detected in the striatum and thalamus, implying that Hap1 is associated with neurodegeneration-sparing regions rather than target lesions in Huntington's disease [6].

High impact information on Hap1

• The alteration of the huntingtin/HAP1/p150(Glued) complex correlates with reduced association of motor proteins with microtubules [7].
• Here, we report that fasting upregulates the expression of Hap1 in the rodent hypothalamus, whereas intracerebroventricular administration of insulin downregulates Hap1 by increasing its degradation through ubiquitination [3].
• These findings provide evidence linking hypothalamic Hap1 to GABA in the stimulation of feeding and suggest that this mechanism is involved in the feeding-inhibitory actions of insulin in the brain [3].
• Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1 [8].
• Transcriptional dysregulation in striatal projection- and interneurons in a mouse model of Huntington's disease: neuronal selectivity and potential neuroprotective role of HAP1 [9].

Biological context of Hap1

• Newborn Hap1(-/-) animals are observed at the expected Mendelian frequency suggesting a non-essential role of HAP-1 during embryogenesis [1].
• Upon reduction of the litter size, some mutants survive into adulthood and display growth retardation with no apparent brain or behavioral abnormalities, suggesting that Hap1 function is essential only for early postnatal feeding behavior [10].
• In addition, we have sequenced a 21,984 base pair (bp) genomic clone encompassing the entire Hap1 gene [2].
• At least three Hap1 transcripts (Hap1-A; Hap1-B; Hap1-C) can be formed by alternative splicing at the 3' end of the gene leading to protein isoforms with novel C-termini [2].
• A recent paper (Sheng et al.,2006) further explores the role of Hap1 in the control of food intake [11].

Anatomical context of Hap1

• In the adult, Hap1 expression is detected not only in the brain but also in the ovary, testis, and the intermediate lobe of the pituitary [12].
• HAP-1 was also strongly associated with an unusual large "dense" organelle [13].
• Results support a role for HAP-1 in vesicle trafficking and organelle movement in mitotic cells and differentiated neurons and implicate HAP-1B as the predominant molecular subtype associated with vesicle membranes in striatal neurons [13].
• In dividing clonal striatal cells, HAP-1 localized to the mitotic spindle apparatus, especially at spindle poles and on vesicles and microtubules of the spindle body [13].
• Electron microscopic study of adult mouse basal forebrain and striatum showed HAP-1 localized to membrane-bound organelles including large endosomes, tubulovesicular structures, and budding vesicles in neurons [13].

Associations of Hap1 with chemical compounds

• We examined the subcellular localization of HAP-1 with an antibody made against the NH2-terminus of the protein [13].
• Hap1 and GABA: thinking about food intake [11].
• HAP1 facilitates effects of mutant huntingtin on inositol 1,4,5-trisphosphate-induced Ca release in primary culture of striatal medium spiny neurons [14].

Other interactions of Hap1

• Hap1(-/-) pups that survive to P8 show signs of starvation including greatly decreased serum leptin levels, decreased brain weight and atrophy of the brain cortical mantel [1].
• However, it is unclear whether, and how, huntingtin-associated proteins are involved in the neurodegeneration in HD [15].
• Huntingtin-associated protein 1 (Hap1) is the first huntingtin interacting protein identified in a yeast two-hybrid screen [10].
• Our present results indicate that HAP1 plays an important role in functional interactions between Htt and InsP3R1 [14].

Analytical, diagnostic and therapeutic context of Hap1

• To investigate the function of Hap1 in development and in the adult mouse, we have examined the expression of Hap1 by northern analysis and in situ hybridization histochemistry [12].
• Chromosomal localization of the Huntingtin associated protein (HAP-1) gene in mouse and humans with radiation hybrid and interspecific backcross mapping [16].

References