ALS2/alsin deficiency in neurons leads to mild defects in macropinocytosis and axonal growth

ArticleinBiochemical and Biophysical Research Communications 370(1):87-92 · June 2008with5 Reads
DOI: 10.1016/j.bbrc.2008.01.177 · Source: PubMed
Loss of function mutations in the ALS2 gene account for a number of juvenile/infantile recessive motor neuron diseases, indicating that its gene product, ALS2/alsin, plays a crucial role in maintenance and survival for a subset of neurons. ALS2 acts as a guanine nucleotide exchange factor (GEF) for the small GTPase Rab5 and is implicated in endosome dynamics in cells. However, the role of ALS2 in neurons remains unclear. To elucidate the neuronal ALS2 functions, we investigate cellular phenotypes of ALS2-deficient primary cultured neurons derived from Als2-knockout (KO) mice. Here, we show that ALS2 deficiency results not only in the delay of axon outgrowth in hippocampal neurons, but also in a decreased level of the fluid phase horseradish peroxidase (HRP) uptake, which represents the activity for macropinocytic endocytosis, in cortical neurons. Thus, ALS2 may act as a modulator in neuronal differentiation and/or development through regulation of membrane dynamics.

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  • ... However, axonal injury in in vitro and in vivo models triggers axonal remodeling in adult neurons that is associated with large amounts of fluid uptake (Tom et al., 2004) consistent with macropinocytosis. Interestingly, some disease associated mutations such as those in ALS2 (in ALS) and γPKC (in spinocerebellar ataxia 14) result in dysregulation of macropinocytosis (Otomo et al., 2008; Yamamoto et al., 2014) suggesting dysfunction of these processes are detrimental to large neurons. ...
  • ... In particular, fusion between early endosomes and macropinosomes is, at least in part, regulated by ALS2 in an ALS2-associated Rab5 GEF activity-dependent manner [124]. Further, ALS2 plays some modulatory roles in axonal outgrowth in neuronal cells [125, 126], and in cytoprotection from oxidative stress-induced insults127128129130. Recently, we have demonstrated that activated Rac1 interacts with ALS2 and induces the relocalization of ALS2 from cytoplasm to membranous compartments; for example , membrane ruffle, macropinosome, and endosome [124]. ...
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  • ... Alsin is a GEF protein predominantly expressed in central nervous system (Devon et al., 2005) that exhibits selective GEF activity on the members of small GTPase Rab5 (Rab5A, Rab5B, and Rab5C;Otomo et al., 2003;Topp et al., 2004). This protein has been involved in receptor trafficking, macropinocytic endocytosis, autophagosome-endolysosomal trafficking and axonal outgrowth (Devon et al., 2006;Hadano et al., 2006Hadano et al., , 2010Jacquier et al., 2006;Kunita et al., 2007;Otomo et al., 2008). A comparison of alsin with other proteins reveals the presence of several interesting motifs. ...
    ALS2, the causative gene product for a number of recessive motor neuron diseases, is a guanine-nucleotide exchange factor for Rab5, and acts as a modulator for endosome dynamics. Recently, we have identified a novel ALS2 homolog, ALS2CL, which is highly homologous to the C-terminal half of ALS2. In this study, we investigate the molecular features of ALS2CL and its functional relationship with... [Show full abstract]
      Mutations in the ALS2 gene cause a number of recessive motor neuron diseases, indicating that the ALS2 protein (ALS2/alsin) is vital for motor neurons. ALS2 acts as a guanine nucleotide exchange factor (GEF) for Rab5 (Rab5GEF) and is involved in endosome dynamics. However, the spatiotemporal regulation of the ALS2-mediated Rab5 activation is unclear. Here we identified an upstream... [Show full abstract]
      February 2011 · FEBS letters
        Loss of ALS2/alsin function accounts for several recessive motor neuron diseases. ALS2 is a Rab5 activator and its endosomal localization is regulated by Rac1 via macropinocytosis. Here, we show that the pathogenic missense ALS2 mutants fail to be localized to Rac1-induced macropinosomes as well as endosomes, which leads to loss of the ALS2 function as a Rab5 activator on endosomes. Further,... [Show full abstract]
          ALS2 is a causative gene for a juvenile autosomal recessive form of motor neuron diseases (MNDs), including amyotrophic lateral sclerosis 2 (ALS2), juvenile primary lateral sclerosis, and infantile-onset ascending hereditary spastic paralysis. These disorders are characterized by ascending degeneration of the upper motor neurons with or without lower motor neuron involvement. Thus far, a total... [Show full abstract]
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