Regulation of endosomal motility and degradation by amyotrophic lateral sclerosis 2/alsin

Chen Lai, Chengsong Xie, Hoon Shim, Jayanth Chandran, Brian W. Howell, Huaibin Cai

    Research output: Contribution to journalArticle

    Abstract

    Dysfunction of alsin, particularly its putative Rab5 guanine-nucleotide- exchange factor activity, has been linked to one form of juvenile onset recessive familial amyotrophic lateral sclerosis (ALS2). Multiple lines of alsin knockout (ALS2-/-) mice have been generated to model this disease. However, it remains elusive whether the Rab5-dependent endocytosis is altered in ALS2-/- neurons. To directly examine the Rab5-mediated endosomal trafficking in ALS2-/- neurons, we introduced green fluorescent protein (GFP)-tagged Rab5 into cultured hippocampal neurons to monitor the morphology and motility of Rab5-associated early endosomes. Here we report that Rab5-mediated endocytosis was severely altered in ALS2-/-neurons. Excessive accumulation of Rab5-positive vesicles was observed in ALS2 -/- neurons, which correlated with a significant reduction in endosomal motility and augmentation in endosomal conversion to lysosomes. Consequently, a significant increase in endosome/lysosome-dependent degradation of internalized glutamate receptors was observed in ALS2-/- neurons. These phenotypes closely resembled the endosomal trafficking abnormalities induced by a constitutively active form of Rab5 in wild-type neurons. Therefore, our findings reveal a negatively regulatory mechanism of alsin in Rab5-mediated endosomal trafficking, suggesting that enhanced endosomal degradation in ALS2-/- neurons may underlie the pathogenesis of motor neuron degeneration in ALS2 and related motor neuron diseases.

    Original languageEnglish (US)
    Article number23
    JournalMolecular Brain
    Volume2
    Issue number1
    DOIs
    StatePublished - 2009

    ASJC Scopus subject areas

    • Molecular Biology
    • Cellular and Molecular Neuroscience

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