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

Neurodegenerative Diseases Research Centre, Graduate School of Medicine, Tokai University, Isehara, Kanagawa 259-1193, Japan.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 06/2008; 370(1):87-92. 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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    • "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., 2006, 2010; Jacquier 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. "
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    ABSTRACT: Small GTPases participate in a broad range of cellular processes such as proliferation, differentiation, and migration. The exchange of GDP for GTP resulting in the activation of these GTPases is catalyzed by a group of enzymes called guanine nucleotide exchange factors (GEFs), of which two classes: Dbl-related exchange factors and the more recently described dedicator of cytokinesis proteins family exchange factors. Increasingly, deregulation of normal GEF activity or function has been associated with a broad range of disease states, including neurodegeneration and neurodevelopmental disorders. In this review, we examine this evidence with special emphasis on the novel role of Rho guanine nucleotide exchange factor (RGNEF/p190RhoGEF) in the pathogenesis of amyotrophic lateral sclerosis. RGNEF is the first neurodegeneration-linked GEF that regulates not only RhoA GTPase activation but also functions as an RNA binding protein that directly acts with low molecular weight neurofilament mRNA 3' untranslated region to regulate its stability. This dual role for RGNEF, coupled with the increasing understanding of the key role for GEFs in modulating the GTPase function in cell survival suggests a prominent role for GEFs in mediating a critical balance between cytotoxicity and neuroprotection which, when disturbed, contributes to neuronal loss.
    Frontiers in Cellular Neuroscience 09/2014; 8. DOI:10.3389/fncel.2014.00282 · 4.29 Impact Factor
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    • "Alsin protects cultured motor neurons from mutant SOD1 toxicity suggesting its neuroprotective role [12]. Overexpression of alsin inhibits mutant SOD1G93A-induced endosomal Rac1 activation and reactive oxygen species production [13,14]. The mutations in alsin may induce a loss of this neuroprotective function by disrupting the endolysomal system and causing an aggregation of immature vesicles and misfolded proteins in neurons [13,14]. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the devastating disease.
    Molecular Neurodegeneration 08/2013; 8(1):28. DOI:10.1186/1750-1326-8-28 · 6.56 Impact Factor
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    • "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 insults [127–130]. "
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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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