Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting

The Journal of clinical investigation (Impact Factor: 13.22). 12/2013; 124(1). DOI: 10.1172/JCI69206
Source: PubMed


Defective neurogenesis in the postnatal brain can lead to many neurological and psychiatric disorders, yet the mechanism behind postnatal neurogenesis remains to be investigated. Huntingtin-associated protein 1 (HAP1) participates in intracellular trafficking in neurons, and its absence leads to postnatal death in mice. Here, we used tamoxifen-induced (TM-induced) Cre recombination to deplete HAP1 in mice at different ages. We found that HAP1 reduction selectively affects survival and growth of postnatal mice, but not adults. Neurogenesis, but not gliogenesis, was affected in HAP1-null neurospheres and mouse brain. In the absence of HAP1, postnatal hypothalamic neurons exhibited reduced receptor tropomyosin-related kinase B (TRKB) levels and decreased survival. HAP1 stabilized the association of TRKB with the intracellular sorting protein sortilin, prevented TRKB degradation, and promoted its anterograde transport. Our findings indicate that intracellular sorting of neurotrophin receptors is critical for postnatal neurogenesis and could provide a therapeutic target for defective postnatal neurogenesis.

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    • "The presence of mutant HTT protein or reduction in HAP1 can impair the Htt/HAP1 interaction and disrupt autophagosome transport potentially leading to neuronal death (51). However, there are multiple lines of evidence that HAP1 is not contributing to the neuropathology of mutant Htt (52–54); instead, mutant Htt may be impacting the normal function of HAP1 (55, 56). To this point, HAP1 is not found in CA3/CA1 of hippocampus, thalamus, or much of the cortical mantel with only small amounts in the somatosensory cortex and caudate/putamen. "
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