Molecular and cellular function of ALS2/alsin: Implication of membrane dynamics in neuronal development and degeneration

Department of Molecular Life Sciences, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.
Neurochemistry International (Impact Factor: 2.65). 07/2007; 51(2-4):74-84. DOI: 10.1016/j.neuint.2007.04.010
Source: PubMed

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 of 12 independent ALS2 mutations, which include a small deletion, non-sense mutation, or missense mutation spreading widely across the entire coding sequence, are reported. They are predicted to result in either premature termination of translation or substitution of an evolutionarily conserved amino acid. Thus, a loss of functions in the ALS2-coded protein accounts for motor dysfunction and/or degeneration in the ALS2-linked MNDs. The ALS2 gene encodes a novel 184kDa protein of 1657 amino acids, ALS2 or alsin, comprising three predicted guanine nucleotide exchange factor (GEF) domains: the N-terminal RCC1-like domain, the central Dbl homology and pleckstrin homology (DH/PH) domains, and the C-terminal vacuolar protein sorting 9 (VPS9) domain. In addition, eight consecutive membrane occupation and recognition nexus (MORN) motifs are noted in the region between DH/PH and VPS9 domains. ALS2 activates Rab5 small GTPase and involves in endosome/membrane trafficking and fusions in the cells, and also promotes neurite outgrowth in neuronal cultures. Further, a neuroprotective role for ALS2 against cytotoxicity; i.e., the mutant Cu/Zn-superoxide dismutase 1 (SOD1)-mediated toxicity, oxidative stress, and excitotoxicity, has recently been implied. This review outlines current understandings of the molecular and cellular functions of ALS2 and its related proteins on safeguarding the integrity of motor neurons, and sheds light on the molecular pathogenesis of MNDs as well as other conditions of neurodegenerative diseases.

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    • "Also, the VAPB (ALS8) mutant shares the ability to form aggregates (Suzuki et al. 2009). Notably, the native alsin protein encoded by the ALS2 gene has been observed to offer protection against Cu,ZnSOD mutational effects in certain cells (Hadano et al. 2007). Many mutations in ALS2 are nonsense mutations that lead to truncations in the gene product, which can destabilize the protein, resulting in proteasomal degradation (Yamanaka et al. 2003). "
    Advanced Understanding of Neurodegenerative Diseases, 12/2011; , ISBN: 978-953-307-529-7
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    • "Based on these findings, mislocalization of ALS2 leads to loss of the ALS2 function as a Rab5 activator on macropinosomes/endosomes, resulting disturbance of the autophagosome and endosome maturation, might account for the ALS2-linked MNDs. Previously, we have shown that loss of the ALS2-associated Rab5GEF activity underlies the pathogenesis of ALS2-linked MNDs [1] [4]. Further, the ALS2-associated Rab5GEF activity is involved in macropinocytosis and the following early endocytic pathway [4] [5] [8]. "
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    ABSTRACT: 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, these mutants lose the competence to enhance the formation of amphisomes, the hybrid-organelle formed upon fusion between autophagosomes and endosomes. Thus, Rac1-induced relocalization of ALS2 might be crucial to exert the ALS2 function associated with the autophagy-endolysosomal degradative pathway.
    FEBS letters 02/2011; 585(5):730-6. DOI:10.1016/j.febslet.2011.01.045 · 3.34 Impact Factor
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    • "ALS2 acts as a guanine nucleotide exchange factor (GEF) for Rab5 (Rab5GEF) and is involved in endosomal membrane trafficking (Hadano et al. 2007, Kunita et al. 2007, Otomo et al. 2003). At least, four of the eight MORN motifs at the C terminus of the Rab5GEF are found to be essential for its function (Hadano et al. 2007). Phosphatidylinositol- 4-phosphate (PtdInsP)2 5-kinases (PtdInsP 5-kinases) catalyze the synthesis of phosphatidylinositol-(4,5)- bisphosphate (PtdIns(4,5)P2), a key component in phosphoinositide (PI) signaling that regulates many cellular processes, for example the opening of stomatal guard cells and salt stress signal transduction (Im et al. 2007, Shimada et al. 2004). "
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    ABSTRACT: Chloroplast biogenesis is tightly linked with embryogenesis and seedling development. A growing body of work has been done on the molecular mechanisms underlying chloroplast development; however, the molecular components involved in chloroplast biogenesis during embryogenesis remain largely uncharacterized. In this paper, we show that an Arabidopsis mutant carrying a T-DNA insertion in a gene encoding a multiple membrane occupation and recognition nexus (MORN)-containing protein exhibits severe defects during embryogenesis, producing abnormal embryos and thereby leading to a lethality of young seedlings. Genetic and microscopic studies reveal that the mutation is allelic to a previously designated Arabidopsis embryo-defective 1211 mutant (emb1211). The emb1211 +/- mutant plants produce approximately 25% of white-colored ovules with abnormal embryos since late globular stage when primary chloroplast biogenesis takes place, while the wild-type plants produce all green ovules. Transmission electron microscopic analysis reveals the absence of normal chloroplast development, both in the mutant embryos and in the mutant seedlings, that contributes to the albinism. The EMB1211 gene is preferentially expressed in developing embryos as revealed in the EMB1211::GUS transgenic plants. Taken together, the data indicate that EMB1211 has an important role during embryogenesis and chloroplast biogenesis in Arabidopsis.
    Physiologia Plantarum 12/2010; 140(4):380-94. DOI:10.1111/j.1399-3054.2010.01407.x · 3.26 Impact Factor
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