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: 3.09). 07/2007; 51(2-4):74-84. DOI: 10.1016/j.neuint.2007.04.010
Source: PubMed


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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    • "However, several questions regarding the pathological mechanism in our patient remain to be answeredabout the PH domain defect of the PLEKHG5 protein and congenital dysfunction in peripheral nervous system via NF-κB signaling pathway. Other human neurodegenerative disease-related genes sharing a PH/RhoGEF domain, such as DNM2, SBF2, and ALS2, could provide important clues for these elusive questions [31-33]. "
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    ABSTRACT: Mutations in the Pleckstrin homology domain-containing, family G member 5 (PLEKHG5) gene has been reported in a family harboring an autosomal recessive lower motor neuron disease (LMND). However, the PLEKHG5 mutation has not been described to cause Charcot-Marie-Tooth disease (CMT). To identify the causative mutation in an autosomal recessive intermediate CMT (RI-CMT) family with childhood onset, whole exome sequencing (WES), histopathology, and lower leg MRIs were performed. Expression and activity of each mutant protein were analyzed. We identified novel compound heterozygous (p.Thr663Met and p.Gly820Arg) mutations in the PLEKHG5 gene in the present family. The patient revealed clinical manifestations of sensory neuropathy. Fatty replacements in the distal lower leg muscles were more severe than in the thigh muscles. Although the symptoms and signs of this patient harboring slow nerve conduction velocities suggested the possibility of demyelinating neuropathy, a distal sural nerve biopsy was compatible with axonal neuropathy. Immunohistochemical analysis revealed that the patient has a low level of PLEKHG5 in the distal sural nerve and an in vitro assay suggested that the mutant proteins have a defect in activating the NF-kappaB signaling pathway. This study identifies compound heterozygous PLEKHG5 mutations as the cause of RI-CMT. We suggest that PLEKHG5 might play a role in the peripheral motor and sensory nervous system. This study expands the phenotypic spectrum of PLEKHG5 mutations.
    Orphanet Journal of Rare Diseases 07/2013; 8(1):104. DOI:10.1186/1750-1172-8-104 · 3.36 Impact Factor
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    • "The ALS2 gene encodes a 184 kDa protein of 1657 amino acids, ALS2 or alsin, comprising three predicted guanine nucleotide exchange factor (GEF) domains: the N-terminal RCC1-like domain (RLD), the central Dbl homology and pleckstrin homology (DH/PH) domain, and the C-terminal vacuolar protein sorting 9 (VPS9) domain [68]. Indeed, it has been shown that ALS2 acts as a GEF for Rab5 [120–122], and regulates endosome fusion and trafficking by activating Rab5 [120, 121, 123] (Figure 1). ALS2 is also involved in Rac1-activated macropinocytosis and the following macropinosome trafficking and fusion [124, 125]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5-10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.
    Neurology Research International 07/2012; 2012(6415):498428. DOI:10.1155/2012/498428
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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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