The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Abstract

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

P53 Protein Modulates Muscle Metabolism and Generates a Non-Genetic Risk Environment that Contributes to Triggering Amyotrophic Lateral Sclerosis

“…We proposed that the overexpression of the parkin protein, especially through its ubiquitin ligase activity, favors neuroprotection after uncontrolled dysregulation of mitochondrial Ca 2+ levels. MAM collapse is a common pathogenesis mechanism in ALS linked to SIGMAR1, SOD1, VAPB, TARDBP, and FUS [78,79]. When analyzing ER mitochondria calcium cycle dynamics (ERMCC) in murine model swith hSOD1-G93A (overexpressing mutant) MNs-as a model for ALS-with sub-sector resolution, using fluorescent calcium imaging, and comparing vulnerable MNs and non-neurons from hSOD1-G93A mice with their non-transgenic littermates, decelerated clearance of cytosolic calcium was associated with hSOD1-G93A.…”

Nearly 30 Years of Animal Models to Study Amyotrophic Lateral Sclerosis: A Historical Overview and Future Perspectives

“…They also participate in the unfolded protein response machine, an ER activity that suppresses accumulation of misfolded proteins to maintain cell viability and function [188]. VAPB has been connected to various neurodegenerative diseases, including ALS [189,190]. Indeed, several mutations of the VAPB gene have been observed in patients with ALS, such as P56S, T46I, del160, D130E, A145V, S160∆, and V234I [58,[191][192][193].…”

Intertwined and Finely Balanced: Endoplasmic Reticulum Morphology, Dynamics, Function, and Diseases

“…Hereditary Spastic Paraplegias Spastin [279] ER tubule regulation [17], ER-endosome MCS [177] Endosomal fission fails at MCS [177] Protrudin [280] ER membrane curvature and tubule fission [281], ER-endosome MCS [204], ER MCS-dependent endosome maturation [125] ER morphology and function dysregulated [225,281] Seipin [282] ER-lipid droplet MCS [283] Axon regeneration impaired [284] Atlastin-1 [285] ER membrane fusion [5] ER morphology dysregulated [17] REEP1 [286] ER membrane curvature [2], ER-mitochondria MCS [106] ER-mitochondria interactions disrupted [106] REEP2 [287] ER membrane curvature regulation [2] ER morphology disrupted [288] KIF5A [195] ER dynamics via kinesin-1 [195] Impaired axonal transport [195] Amyotrophic Lateral Sclerosis VAPB [289] MCS between ER and many organelles (reviewed [290,291]) ER morphology dysregulated [292][293][294][295], ER-mitochondria MCS [296,297],interactions between VAPB and oxysterol binding protein (OSBP) perturbed [298] Reticulon 4 [299] ER membrane curvature [2] Chaperone protein disulfide isomerase (PDI) distribution altered [299] Sigma-1 Receptor [300]<...>…”

“…Mutations in KIF5A could conceivably affect this pathway. The disruption of ER–endosomal interactions also affects endosomal sorting and leads to lysosomal defects ( Section 2.2 .6 and 3.1.2), and this is frequently linked to diseases such as HSP and ALS ( Table 1 ), where it can be caused by mutations in spastin, strumpelin, REEP1 [ 177 ], and VAPB, as described elsewhere in this special issue [ 291 ].…”

“…The ALS mutant form of VAPB leads to an altered MCS with the outer mitochondrial membrane protein PTPIP51, perturbing Ca 2+ uptake at these MCSs [ 296 ]. Many other ALS mutations affect ER–mitochondrial contacts, such as those in VAPB (see reviews by Chen et al and Borgese et al in this issue [ 275 , 291 ]).…”