Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities

Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2006; 103(25):9595-600. DOI: 10.1073/pnas.0510197103
Source: PubMed


ALS2 is an autosomal recessive form of spastic paraparesis (motor neuron disease) with juvenile onset and slow progression caused by loss of function of alsin, an activator of Rac1 and Rab5 small GTPases. To establish an animal model of ALS2 and derive insights into the pathogenesis of this illness, we have generated alsin-null mice. Cytosol from brains of Als2(-/-) mice shows marked diminution of Rab5-dependent endosome fusion activity. Furthermore, primary neurons from Als2(-/-) mice show a disturbance in endosomal transport of insulin-like growth factor 1 (IGF1) and BDNF receptors, whereas neuronal viability and endocytosis of transferrin and dextran seem unaltered. There is a significant decrease in the size of cortical motor neurons, and Als2(-/-) mice are mildly hypoactive. Altered trophic receptor trafficking in neurons of Als2(-/-) mice may underlie the histopathological and behavioral changes observed and the pathogenesis of ALS2.

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Available from: Paul C Orban, Aug 21, 2014
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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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    • "Furthermore, a recent study found that neurons differentiated from iPSC cells of C9ORF72 expansion carriers showed increased sensitivity to chemical inhibitors of endosomal-lysosomal and autophagy pathways compared with controls (Almeida et al., 2013). Dysfunction of vesicular trafficking processes such as endosomal-lysosomal trafficking and autophagy may be a pathological consequence of the C9ORF72 hexanucleotide repeat and has been implicated in other genetic forms of motor neuron degeneration and FTD (Devon et al., 2006; Filimonenko et al., 2007; Ju et al., 2009; Tumbarello et al., 2013; Wild et al., 2011). A collection of studies analyzing neurons differentiated from iPSCs derived from pathological expansion carriers point toward a gain-of-function mechanism resulting from toxic repeat-containing RNA inclusions and insoluble peptide aggregates generated by non-AUG mediated translation of the hexanucleotide repeat (Almeida et al., 2013; Ash et al., 2013; DeJesus-Hernandez et al., 2011; Donnelly et al., 2013; Lagier-Tourenne et al., 2013; Mori et al., 2013a, 2013b; Sareen et al., 2013). "
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    ABSTRACT: An intronic G4C2 hexanucleotide repeat expansion in C9ORF72 is a major cause of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Several mechanisms including RNA toxicity, repeat-associated non-AUG translation mediated dipeptide protein aggregates, and haploinsufficiency of C9orf72 have been implicated in the molecular pathogenesis of this disorder. The aims of this study were to compare the use of two different Southern blot probes for detection of repeat expansions in an amyotrophic lateral sclerosis and frontotemporal lobar degeneration pathological cohort and to determine the levels of C9orf72 transcript variants and protein isoforms in patients versus control subjects. Our Southern blot studies identified smaller repeat expansions (250-1800 bp) that were only detectable with the flanking probe highlighting the potential for divergent results using different Southern blotting protocols that could complicate genotype-phenotype correlation studies. Further, we characterize a new C9orf72 antibody and show for the first time decreased C9orf72 protein levels in the frontal cortex from patients with a pathological hexanucleotide repeat expansion. These data suggest that a reduction in C9orf72 protein may be a consequence of the disease.
    Neurobiology of aging 01/2014; 35(7). DOI:10.1016/j.neurobiolaging.2014.01.016 · 5.01 Impact Factor
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    • "Mouse (Gurney et al. 1994), and others reviewed in (Bruijn et al. 2004) Transgenic SOD1 mutant variants Zebrafish (Lemmens et al. 2007; Ramesh et al. 2010) Alsin (ALS2) Alsin KO mouse Mouse (Devon et al. 2006) Alsin knock down Zebrafish (Gros-Louis et al. 2008) FUS (ALS6) Transgenic human WT FUS Mouse (Mitchell et al. 2013) Knock down and transgenic mutant FUS Zebrafish (Kabashi et al. 2010) "
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    ABSTRACT: This review article is focused on the research progress made utilizing the wobbler mouse as animal model for human motor neuron diseases, especially the amyotrophic lateral sclerosis (ALS). The wobbler mouse develops progressive degeneration of upper and lower motor neurons and shows striking similarities to ALS. The cellular effects of the wobbler mutation, cellular transport defects, neurofilament aggregation, neuronal hyperexcitability and neuroinflammation closely resemble human ALS. Now, 57 years after the first report on the wobbler mouse we summarize the progress made in understanding the disease mechanism and testing various therapeutic approaches and discuss the relevance of these advances for human ALS. The identification of the causative mutation linking the wobbler mutation to a vesicle transport factor and the research focussed on the cellular basis and the therapeutic treatment of the wobbler motor neuron degeneration has shed new light on the molecular pathology of the disease and might contribute to the understanding the complexity of ALS.
    MGG Molecular & General Genetics 03/2013; 288(5-6). DOI:10.1007/s00438-013-0741-0 · 2.73 Impact Factor
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