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.
Highlights
The prevalence of neurodegenerative diseases is increasing due to an increase in aging population, but the molecular mechanism remains elusive
We provide evidence that Hap1 associates with Breakpoint cluster region protein (Bcr)
The interaction of Hap1 with Bcr was initially identified via mass spectrometry analysis of associated proteins with microtubules precipitated by taxol and verified by immunoprecipitation of these two proteins (Fig. 1)
Summary
The prevalence of neurodegenerative diseases is increasing due to an increase in aging population, but the molecular mechanism remains elusive. Neurodegenerative diseases such as Alzheimer’s disease (AD) and Huntington’s disease (HD) are characterized by progressive neuropsychiatric dysfunction and loss of specific subtypes of neurons. There are distinct neuropathology and clinical profiles among these diseases, many similarities in pathological pathways were reported [1]. One of the common pathogenic events in neurodegenerative. HAP1 Interacts with BCR in Neuronal Differentiation PLOS ONE | DOI:10.1371/journal.pone.0116372 February 11, 2015
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