Han SM, Tsuda H, Yang Y, Vibbert J, Cottee P, Lee SJ, Winek J, Haueter C, Bellen HJ, Miller MA. Secreted VAPB/ALS8 major sperm protein domains modulate mitochondrial localization and morphology via growth cone guidance receptors. Dev Cell. 2012 Feb 14;22(2):348-62. PubMed.
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I think this is a great paper that unravels a novel role for VAMP/synaptobrevin-associated protein B (VAPB) with great precision. The paper again illustrates the power of Drosophila and C. elegans as animal models for identifying functional roles of proteins and illuminating potential disease pathways.
The questions raised by the P56S-VAPB mutation are essentially the same as those raised by mutations in genes linked to other ALS forms, as well as to other neurodegenerative disorders: What is the function of the mutated protein? Does the disease result from a loss of its normal function or a gain of toxic activity? What is the role of protein aggregation? What determines the delayed onset of disease, and to what extent do disease pathways overlap with those in other ALS forms? And, most importantly, how to stop or prevent disease?
Several lines of evidence indicate that mutant VAPB, at least in part, may operate in a dominant-negative way by recruiting wild-type VAPB to inclusions. the paper by Han et al. provides one potential mechanism by which loss of VAPB function in motor neurons results in reduced performance of skeletal muscle.
This work follows a provocative study by the same groups published in Cell in 2008, indicating that a fragment of the Drosophila VAPB homologue containing the major sperm protein (MSP) domain may act as a paracrine factor released by motor neurons at the neuromuscular junctions. Now, Han et al. show that loss of VAPB in motor neurons in both Drosophila and C. elegans results in structural and functional mitochondrial abnormalities in the target muscles. Importantly, the same effect was also observed after mutant VAP overexpression in the motor neurons, supporting the dominant-negative mode of action of mutant VAP.
In an elegant series of experiments, the authors further show that the MSP domain of VAPB binds to a Robo and a Lar-receptor to control mitochondrial localization via the regulation of the actin skeleton. As indicated in the conclusion scheme by the authors (Fig. 8C), one major unresolved question is how the VAP-MSP fragment reaches the extracellular space. Another question is whether a similar mechanism operates in vertebrates and, in particular, in mammals. This question awaits the analysis of VAPB-knockout mice.
Another problem is that the authors’ model predicts that the functional defects resulting from VAPB deficiency in motor neurons occur in the muscle fibers. However, EMG and muscle biopsy (Marques et al., 2006) point to a neurogenic basis of the disease, consistent with the diagnosis of ALS, and implying functional loss and degeneration of motor neurons or their axons (rather than muscle fibers) as the prime event in the disease. Nevertheless several mechanisms can be envisaged by which loss of motor neuron VAPB contributes to muscle weakness not only in VAPB-ALS, but also in other ALS forms.
Remarkably, a recent study has suggested a mechanism by which mutant VAPB may cause mitochondrial abnormalities in a cell-autonomous way in motor neurons (De Vos et al., 2011). This study shows that VAPB may interact with the mitochondrial protein PTPIP51 to regulate its interaction with the endoplasmic reticulum and calcium homeostasis. According to this study, mutant VAPB disturbs this interaction and alters calcium homeostasis. In regard to that study, I would like to point out that we do not see ultrastructural mitochondrial abnormalities in motor neurons of our transgenic mice that overexpress mutant VAPB. The mice develop numerous VAPB "aggregates" in motor neurons, but the aggregates seem to be rather harmless, which is consistent with data from another study with VAPB transgenic mice (Tudor et al., 2010).
References:
Marques VD, Barreira AA, Davis MB, Abou-Sleiman PM, Silva WA, Zago MA, Sobreira C, Fazan V, Marques W. Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle Nerve. 2006 Dec;34(6):731-9. PubMed.
De Vos KJ, Mórotz GM, Stoica R, Tudor EL, Lau KF, Ackerley S, Warley A, Shaw CE, Miller CC. VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum Mol Genet. 2011 Dec 13; PubMed.
Tudor EL, Galtrey CM, Perkinton MS, Lau KF, De Vos KJ, Mitchell JC, Ackerley S, Hortobágyi T, Vámos E, Leigh PN, Klasen C, McLoughlin DM, Shaw CE, Miller CC. Amyotrophic lateral sclerosis mutant vesicle-associated membrane protein-associated protein-B transgenic mice develop TAR-DNA-binding protein-43 pathology. Neuroscience. 2010 May 19;167(3):774-85. Epub 2010 Feb 24 PubMed.
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