A Mutation in the Vesicle-Trafficking Protein VAPB Causes Late-Onset Spinal Muscular Atrophy and Amyotrophic Lateral Sclerosis

Human Genome Research Center, Department of Biology, Biosciences Institute, São Paulo University, São Paulo, Brazil.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2004; 75(5):822-31. DOI: 10.1086/425287
Source: PubMed


Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.

Download full-text


Available from: Agnes Lumi Nishimura,
  • Source
    • "Frontiers in Neuroscience | www.frontiersin.org 2 October 2015 VABP ( ALS8 ; Nishimura et al., 2004 "
    [Show abstract] [Hide abstract]
    ABSTRACT: The wobbler mouse is an animal model for human motor neuron disease, such as amyotrophic lateral sclerosis (ALS). The spontaneous, recessive wobbler mutation causes degeneration of upper and lower motor neurons leading to progressive muscle weakness with striking similarities to the ALS pathology. The wobbler mutation is a point mutation affecting Vps54, a component of the Golgi-associated retrograde protein (GARP) complex. The GARP complex is a ubiquitously expressed Golgi-localized vesicle tethering complex, tethering endosome-derived vesicles to the trans Golgi network. The wobbler point mutation leads to a destabilization of the Vps54 protein and thereby the whole GARP complex. This effectuates impairments of the retrograde vesicle transport, mis-sorting of Golgi- and endosome localized proteins and on the long run defects in Golgi morphology and function. It is currently largely unknown how the destabilization of the GARP complex interferes with the pathological hallmarks, reported for the wobbler motor neuron degeneration, like neurofilament aggregation, axonal transport defects, hyperexcitability, mitochondrial dysfunction, and how these finally lead to motor neuron death. However, the impairments of the retrograde vesicle transport and the Golgi-function appear to be critical phenomena in the molecular pathology of the wobbler motor neuron disease.
    Frontiers in Neuroscience 11/2015; 9:381. DOI:10.3389/fnins.2015.00381 · 3.66 Impact Factor
  • Source
    • "The decrease in synaptic bouton number with a concomitant increase in bouton volume in iav 1 is reminiscent of the phenotype observed in larvae lacking genes such as wingless (Miech et al., 2008; Packard et al., 2002), vapb (encoding Vesicle Associated Membrane Protein-B) (Nishimura et al., 2004; Pennetta et al., 2002), futsch (the fly ortholog of the gene encoding mammalian microtubule associated protein-1b, MAP-1b) (Roos et al., 2000; Zhang et al., 2001), and pp2A-B 0 (a subunit of the PP2A protein phosphatase) (Viquez et al., 2006). Because diminished stability of presynaptic microtubules underlies the synaptic defects in these mutants, we assessed the structure of the presynaptic microtubules in iav 1 . "

    Neuron 11/2014; 84(4):764-777. · 15.05 Impact Factor
  • Source
    • "A substitution mutation in the highly conserved proline residue at the 56 th position to Serine in the MSP domain results in a protein that forms cellular aggregates (Nishimura et al., 2004; Teuling et al., 2007). Patients with this mutation show spectrum of symptoms including typical ALS, slow progressive ALS and Spinal Muscular Atrophy (SMA) (Nishimura et al., 2004). This suggests that other genetic factors might decide the phenotypic outcome of the mutation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective death of motor neurons. In 5–10% of the familial cases, the disease is inherited because of mutations. One such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions. We have conducted a reverse genetic screen to identify interactors of Drosophila VAPB. We screened 2635 genes and identified 103 interactors, of which 45 were enhancers and 58 were suppressors of VAPB function. Interestingly, the screen identified known ALS loci – TBPH, alsin2 and SOD1. Also identified were genes involved in cellular energetics and homeostasis which were used to build a gene regulatory network of VAPB modifiers. One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S) expression in neurons. A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2) that negatively regulates TOR signaling as also by reduction of S6K activity. In comparison, the small bouton phenotype associated with VAP(wt) expression was reversed with Tsc1 knock down as well as S6K-CA expression. Tor therefore interacts with both VAP(wt) and VAP(P58S), but in a contrasting manner. Reversal of VAP(P58S) bouton phenotypes in larvae fed with the TOR inhibitor Rapamycin suggests upregulation of TOR signaling in response to VAP(P58S) expression. The VAPB network and further mechanistic understanding of interactions with key pathways, such as the TOR cassette, will pave the way for a better understanding of the mechanisms of onset and progression of motor neuron disease.
    Biology Open 11/2014; 3(11):1127-38. DOI:10.1242/bio.201410066 · 2.42 Impact Factor
Show more