Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting
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.
Available from: Will Kenkel
- "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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ABSTRACT: Blood oxygen level dependent (BOLD) imaging in awake mice was used to identify differences in brain activity between wild-type, HETzQ175, and HOMzQ175 genotypes in response to the odor of almond. The study was designed to see how alterations in the huntingtin gene in a mouse model of Huntington's disease would affect the perception and processing of almond odor, an evolutionarily conserved stimulus with high emotional and motivational valence. Moreover, the mice in this study were "odor naïve," i.e., never having smelled almond or any nuts. Using a segmented, annotated MRI atlas of the mouse and computational analysis, 17 out of 116 brain regions were identified as responding differently to almond odor across genotypes. These regions included the glomerulus of the olfactory bulb, forebrain cortex, anterior cingulate, subiculum, and dentate gyrus of the hippocampus, and several areas of the hypothalamus. In many cases, these regions showed a gene-dose effect with HETzQ175 mice showing a reduction in brain activity from wild-type that is further reduced in HOMzQ175 mice. Conspicuously absent were any differences in brain activity in the caudate/putamen, thalamus, CA3, and CA1 of the hippocampus and much of the cortex. The glomerulus of the olfactory bulb in HOMzQ175 mice showed a reduced change in BOLD signal intensity in response to almond odor as compared to the other phenotypes suggesting a deficit in olfactory sensitivity.
Frontiers in Neurology 06/2014; 5:94. DOI:10.3389/fneur.2014.00094
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ABSTRACT: The neurotensin receptor-3 also known as sortilin belongs to the new receptor family of vacuolar protein sorting 10 protein domain containing receptors. Growing evidence show that the vacuolar protein sorting 10 protein domain family is implicated as a genetic risk factor for neurodegenerative diseases, including Alzheimer's disease, frontotemporal lobar degeneration, and Parkinson's disease, in addition to links associated with type 2 diabetes mellitus, lysosomal disorders, cardiovascular disease and atherosclerosis. In fact, sortilin expression is elevated in many human cell lines controlling the trafficking and release of neurotrophins. Hence, not surprisingly the imbalance of neurotrophin signaling is implicated in several human diseases. The fine regulation of the growth factor, brain derived nerve factor by sortilin mediates both neuronal and tumor cell survival, whereas sortilin mediated beta secretase-1 trafficking increases the cleavage of the beta-amyloid precursor protein in Alzheimer's disease. Perturbation of the autocrine/paracrine loop of neurotrophins in combination with the cell surface interaction of sortilin with neurotensin receptor 1 or 2 or tyrosine kinase receptor A or B are dramatically upregulated in both neurodegenerative diseases and cancer. In cardiovascular diseases, the circulatory low-density lipoprotein is closely correlated with sortilin expression in hepatocytes. Herein, this review discusses the multifaceted role played by sortilin and its interacting partners in human disease which could be interesting novel target(s) in drug discovery. Nevertheless, completely challenging the function of sortilin could prove unfavorable given the important universal role of sortilin plays in the body. Hence, metabolism disorders could be relieved with specific targeted therapeutic challenge of sortilin function.
CNS & neurological disorders drug targets 05/2014; 13(8). DOI:10.2174/1871527313666141023151642 · 2.63 Impact Factor
Available from: Yung-Feng Lin
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ABSTRACT: Alterations in microtubule-dependent trafficking and certain signaling pathways in neuronal cells represent critical pathogenesis in neurodegenerative diseases. Huntingtin (Htt)-associated protein-1 (Hap1) is a brain-enriched protein and plays a key role in the trafficking of neuronal surviving and differentiating cargos. Lack of Hap1 reduces signaling through tropomyosin-related kinases including extracellular signal regulated kinase (ERK), resulting in inhibition of neurite outgrowth, hypothalamic dysfunction and postnatal lethality in mice. To examine how Hap1 is involved in microtubule-dependent trafficking and neuronal differentiation, we performed a proteomic analysis using taxol-precipitated microtubules from Hap1-null and wild-type mouse brains. Breakpoint cluster region protein (Bcr), a Rho GTPase regulator, was identified as a Hap1-interacting partner. Bcr was co-immunoprecipitated with Hap1 from transfected neuro-2a cells and co-localized with Hap1A isoform more in the differentiated than in the nondifferentiated cells. The Bcr downstream effectors, namely ERK and p38, were significantly less activated in Hap1-null than in wild-type mouse hypothalamus. In conclusion, Hap1 interacts with Bcr on microtubules to regulate neuronal differentiation.
PLoS ONE 02/2015; 10(2):e0116372. DOI:10.1371/journal.pone.0116372 · 3.23 Impact Factor
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