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

ABSTRACT 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.

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Available from: Agnes Lumi Nishimura, Sep 26, 2015
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    • "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
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    • "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. "
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    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
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    • "A Phe56 to Ser mutation in the MSP domain of VAPB causes amyotrophic lateral sclerosis (ALS) type 8 in humans, transmitted in an autosomally dominant manner [29]. Subsequently, another VAPB mutation in the same region (Thr46 to Ile) was identified in a British ALS patient [30]. "
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    ABSTRACT: Background FAF1 is a ubiquitin-binding adaptor for the p97 ATPase and belongs to the UBA-UBX family of p97 cofactors. p97 converts the energy derived from ATP hydrolysis into conformational changes of the p97 hexamer, which allows the dissociation of its targets from cellular structures or from larger protein complexes to facilitate their ubiquitin-dependent degradation. VAPB and the related protein VAPA form homo- and heterodimers that are anchored in the endoplasmic reticulum membrane and can interact with protein partners carrying a FFAT motif. Mutations in either VAPB or p97 can cause amyotrophic lateral sclerosis, a neurodegenerative disorder that affects upper and lower motor neurons. Results We show that FAF1 contains a non-canonical FFAT motif that allows it to interact directly with the MSP domain of VAPB and, thereby, to mediate VAPB interaction with p97. This finding establishes a link between two proteins that can cause amyotrophic lateral sclerosis when mutated, VAPB/ALS8 and p97/ALS14. Subsequently, we identified a similar FFAT-like motif in the ASNA1 subunit of the transmembrane-domain recognition complex (TRC), which in turn mediates ASNA1 interaction with the MSP domain of VAPB. Proteasome inhibition leads to the accumulation of ubiquitinated species in VAPB immunoprecipitates and this correlates with an increase in FAF1 and p97 binding. We found that VAPB interaction with ubiquitinated proteins is strongly reduced in cells treated with FAF1 siRNA. Our efforts to determine the identity of the ubiquitinated targets common to VAPB and FAF1 led to the identification of RPN2, a subunit of an oligosaccharyl-transferase located at the endoplasmic reticulum, which may be regulated by ubiquitin-mediated degradation. Conclusions The FFAT-like motifs we identified in FAF1 and ASNA1 demonstrate that sequences containing a single phenylalanine residue with the consensus (D/E)(D/E)FEDAx(D/E) are also proficient to mediate interaction with VAPB. Our findings indicate that the repertoire of VAPB interactors is more diverse than previously anticipated and link VAPB to the function of ATPase complexes such as p97/FAF1 and ASNA1/TRC.
    BMC Biology 05/2014; 12(1):39. DOI:10.1186/1741-7007-12-39 · 7.98 Impact Factor
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