Hap1, short for huntingtin-associated protein 1, is significantly involved in intracellular trafficking. It binds to microtubule-dependent transporters for anterograde or retrograde transport, and associates with various organelles and membrane receptors. Hap1 is enriched in neurons, and its function may be related to the selective neuropathology in Huntington's disease. Hap1-related research models, especially cell-based models, are valuable for studying its functions [1,2].

Hap1 knockout (KO) studies have revealed multiple functions. In neurons, Hap1 KO abolishes BDNF and TrkB internalization, impairs TrkB downstream signalling pathways like ERK, Akt and PLCγ-1, and affects the proliferation of cerebellar granule cells, suggesting its key role in BDNF and receptor endocytosis, and in promoting neuronal survival and proliferation [3]. In acute lymphoblastic leukemia (ALL), knocking down Hap1 confers l-asparaginase resistance by downregulating the calpain-1-Bid-caspase-3/12 pathway, indicating Hap1 as a potential biomarker for l-asparaginase-resistant ALL [4]. In a pentylenetetrazole rat model of epilepsy, disrupting the HAP1/14-3-3 complex decreases the strength of GABAAR-mediated inhibitory synaptic transmission, suggesting it as a possible drug target for epilepsy [5]. In Angelman syndrome (AS) mouse models, knocking down HAP1 alleviated aberrant autophagy in primary neurons, and autophagy inhibition in AS mice partially alleviated a social interaction deficit [6].

In conclusion, Hap1 plays essential roles in multiple biological processes including intracellular trafficking, endocytosis of BDNF and its receptors, regulation of autophagy, and influencing signalling pathways related to cell survival, proliferation, and apoptosis. The gene knockout studies in mouse models have provided crucial insights into Hap1's functions in diseases such as Huntington's disease, ALL, epilepsy, and Angelman syndrome, which may contribute to the development of new therapeutic strategies for these conditions.