Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis

Kabashi, Edor; Oussini, Hajer El; Bercier, Valérie; Gros‐Louis, François; Valdmanis, Paul N.; McDearmid, Jonathan R.; Mejier, Inge A.; Dion, Patrick A.; Dupré, Nicolas; Hollinger, David Y.; Sinniger, Jérôme; Dirrig‐Grosch, Sylvie; Camu, William; Meininger, Vincent; Loeffler, Jean‐Philippe; Frydman, René; Drapeau, Pierre; Rouleau, Guy A.; Dupuis, Luc

doi:10.1093/hmg/ddt080

Cited by 80 publications

(83 citation statements)

References 43 publications

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“…Mice were followed weekly for general health, neurological symptoms, body weight, grip test and accelerating rotarod performances starting from weaning (4 weeks of age) until 22 months of age as described previously [39]. Briefly, mouse motor performance was assessed using rotarod (Ugobasile model 7650).…”

Section: Methodsmentioning

confidence: 99%

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

et al. 2017

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Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1687-9) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

et al. 2017

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“…It remains unclear whether the disease results from a dominant-negative effect of the mutant protein or from haploinsufficiency (Kabashi et al, 2013; Papiani et al, 2012; Teuling et al, 2007). Elucidating the impact of VAP loss-of-function may thus illuminate mechanisms of disease in addition to providing insights into fundamental aspects of lipid dynamics.…”

Section: Introductionmentioning

confidence: 99%

Endosome-ER Contacts Control Actin Nucleation and Retromer Function through VAP-Dependent Regulation of PI4P

Dong

Saheki

Swarup

et al. 2016

Cell

335

368

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SUMMARY VAP (VAPA and VAPB) is an evolutionarily conserved endoplasmic reticulum (ER)-anchored protein that helps generate tethers between the ER and other membranes through which lipids are exchanged across adjacent bilayers. Here, we report that by regulating PI4P levels on endosomes, VAP affects WASH-dependent actin nucleation on these organ-elles and the function of the retromer, a protein coat responsible for endosome-to-Golgi traffic. VAP is recruited to retromer budding sites on endosomes via an interaction with the retromer SNX2 subunit. Cells lacking VAP accumulate high levels of PI4P, actin comets, and trans-Golgi proteins on endosomes. Such defects are mimicked by downregulation of OSBP, a VAP interactor and PI4P transporter that participates in VAP-dependent ER-endosomes tethers. These results reveal a role of PI4P in retromer-/WASH-dependent budding from endosomes. Collectively, our data show how the ER can control budding dynamics and association with the cyto-skeleton of another membrane by direct contacts leading to bilayer lipid modifications.

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“…ALS8 is caused by mutation in VAPB [8], a small tail-anchored ER membrane protein that is member of a conserved VAP (VAMP/synaptobrevin-associated proteins) family of proteins. Several VAPB mutations have been identified, but so far only a P56S mutation is yet known to co-segregate with disease [8,9]. VAP proteins are characterized by an N-terminal MSP (major sperm protein) domain, a coiled-coil motif, and a C-terminal transmembrane region, and in mammals consists of two genes, VAPA and VAPB [10,11].…”

Section: Introductionmentioning

confidence: 99%

Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

Kuijpers

Dis

Haasdijk

et al. 2013

acta neuropathol commun

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BackgroundProtein aggregation and the formation of intracellular inclusions are a central feature of many neurodegenerative disorders, but precise knowledge about their pathogenic role is lacking in most instances. Here we have characterized inclusions formed in transgenic mice carrying the P56S mutant form of VAPB that causes various motor neuron syndromes including ALS8.ResultsInclusions in motor neurons of VAPB-P56S transgenic mice are characterized by the presence of smooth ER-like tubular profiles, and are immunoreactive for factors that operate in the ER associated degradation (ERAD) pathway, including p97/VCP, Derlin-1, and the ER membrane chaperone BAP31. The presence of these inclusions does not correlate with signs of axonal and neuronal degeneration, and axotomy leads to their gradual disappearance, indicating that they represent reversible structures. Inhibition of the proteasome and knockdown of the ER membrane chaperone BAP31 increased the size of mutant VAPB inclusions in primary neuron cultures, while knockdown of TEB4, an ERAD ubiquitin-protein ligase, reduced their size. Mutant VAPB did not codistribute with mutant forms of seipin that are associated with an autosomal dominant motor neuron disease, and accumulate in a protective ER derived compartment termed ERPO (ER protective organelle) in neurons.ConclusionsThe data indicate that the VAPB-P56S inclusions represent a novel reversible ER quality control compartment that is formed when the amount of mutant VAPB exceeds the capacity of the ERAD pathway and that isolates misfolded and aggregated VAPB from the rest of the ER. The presence of this quality control compartment reveals an additional level of flexibility of neurons to cope with misfolded protein stress in the ER.

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Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis

Cited by 80 publications

References 43 publications

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

Endosome-ER Contacts Control Actin Nucleation and Retromer Function through VAP-Dependent Regulation of PI4P

Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

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