VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis

Department of Neuroscience, MRC Centre for Neurodegeneration Research, Institute of Psychiatry, King’s College London, London SE5 8AF, UK.
Human Molecular Genetics (Impact Factor: 6.39). 11/2011; 21(6):1299-311. DOI: 10.1093/hmg/ddr559
Source: PubMed


A proline to serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein
B (VAPB) causes some dominantly inherited familial forms of motor neuron disease including amyotrophic lateral sclerosis (ALS)
type-8. VAPB is an integral endoplasmic reticulum (ER) protein whose amino-terminus projects into the cytosol. Overexpression
of ALS mutant VAPBP56S disrupts ER structure but the mechanisms by which it induces disease are not properly understood. Here
we show that VAPB interacts with the outer mitochondrial membrane protein, protein tyrosine phosphatase-interacting protein
51 (PTPIP51). ER and mitochondria are both stores for intracellular calcium (Ca2+) and Ca2+ exchange between these organelles occurs at regions of ER that are closely apposed to mitochondria. These are termed mitochondria-associated
membranes (MAM). We demonstrate that VAPB is a MAM protein and that loss of either VAPB or PTPIP51 perturbs uptake of Ca2+ by mitochondria following release from ER stores. Finally, we demonstrate that VAPBP56S has altered binding to PTPIP51 and
increases Ca2+ uptake by mitochondria following release from ER stores. Damage to ER, mitochondria and Ca2+ homeostasis are all seen in ALS and we discuss the implications of our findings in this context.

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    • "Secreted MSP domain of VAP regulates mitochondrial morphology (Han et al., 2012) and VAP(P56S) mutant is known to affect anterograde transport of mitochondria along the axons (Mórotz et al., 2012). VAP interacts with PTPIP51 and helps in maintaining calcium homeostasis (De Vos et al., 2012). Neuronal loss of VAPB affects reduces ATP levels, altered fat metabolism in muscles and this is mediated via DAF-16 (Han et al., 2013b). "
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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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    • "However, the forms share clinical features. The suggested causative factors for the motor neuron degeneration include oxidative stress, neuroimmune reactions, protein aggregation (Boillée et al., 2006) and mitochondrial abnormalities such as disturbed calcium homeostasis (Jaiswal and Keller, 2009; De Vos et al., 2012) and dysfunctional axonal transport (De Vos et al., 2007). Nevertheless, the mechanism is yet to be identified. "
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    ABSTRACT: In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial in vitro and in vivo evidence has accumulated demonstrating that localization of mutSOD1 to the mitochondrial intermembrane space (IMS) inevitably leads to impairment of mitochondrial functions. However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.
    Frontiers in Cellular Neuroscience 05/2014; 8:126. DOI:10.3389/fncel.2014.00126 · 4.29 Impact Factor
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    • "VAPB localization is directed by PTPIP51 to mitochondria-associated membranes. VABP and PTPIP51 are involved in calcium exchange between the endoplasmic reticulum (ER) and mitochondria (De Vos et al., 2012). "
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    ABSTRACT: Mutations in the gene encoding vesicle-associated membrane protein (VAPB) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. The VAPB gene is mapped to chromosome number 20 and can be found at cytogenetic location 20q13.33 of the chromosome. VAPB is seen to play a significant role in the unfolded protein response (UPR), which is a process that suppresses the accumulation of unfolded proteins in the endoplasmic reticulum. Earlier studies have reported two points; which we have analyzed in our study. Firstly, the mutation P56S in the VAPB is seen to increase the stability of the protein and secondly, the mutation P56S in VAPB is seen to interrupt the functioning of the gene and loses its ability to be involved in the activation of the IRE1/XBP1 pathway which leads to ALS. With correlation on the previous research studies on the stability of this protein, we carried out Molecular dynamics (MD) simulation. We analyzed the SNP results of 17 nsSNPs obtained from dbSNP using SIFT, polyphen, I-Mutant, SNP&GO, PhDSNP and Mutpred to predict the role of nsSNPs in VAPB. MD simulation is carried out and plots for RMSD, RMSF, Rg, SASA, H-bond and PCA are obtained to check and prove the stability of the wild type and the mutant protein structure. The protein is checked for its aggregation and the results obtained show changes in the protein structure that might result in the loss of function.
    Journal of Theoretical Biology 03/2014; 354. DOI:10.1016/j.jtbi.2014.03.027 · 2.12 Impact Factor
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