Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons

Abstract

The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) mice that heterologously express human wild-type (WT) and P56S VAPB under the control of a pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein expression were observed in the CSMNs and SMNs of P56S VAPB Tg mice. However, only a progressive loss of CSMNs but not SMNs was found in P56S VAPB Tg mice. In SMNs, P56S VAPB promoted a rather selective translocation of VAPB protein onto the postsynaptic site of C-boutons that altered the morphology of C-boutons and impaired the spontaneous rhythmic discharges of SMNs. Therefore, these findings provide new pathophysiological mechanisms of P56S VAPB that differentially affect the function and survival of CSMNs and SMNs in ALS8.

Nucleocytoplasmic transport defect in a North American patient with ALS8

“…Our results contrast with studies done in overexpression cell models where the VAPB mutation was found to result in the reduced activation of UPR (IRE1a and ATF6) 6, 9. In transgenic mouse models of P56S, there was evidence of increased ER stress, as we saw in patient cells 8, 17. The mRNA expression profile in our patient showed a pattern indicative of ER stress, with an increase in chaperones, PERK pathway genes, and spliced XBP1, as has been reported in other disease models 18, 19.…”

“…However, an ALS8 motor neuron cell model was found to have reduced levels of the P56S mutant protein without mislocalization 7. Some studies have shown that mutant VAPB results in endoplasmic reticulum (ER) stress, and unfolded protein response (UPR) activation, while other studies have shown a loss of IRE1a activated UPR with the P56S mutation 6, 8, 9. The effects of P56S mutation on ER stress and UPR activation remains to be further defined in patient cells.…”

Neuregulin‐1 is concentrated in the postsynaptic subsurface cistern of C‐bouton inputs to α‐motoneurons and altered during motoneuron diseases

“…Other morphological alterations of the subsurface cisterns also appear to be present in ALS‐linked mutations of vesicle‐associated membrane protein‐associated protein B, which is abnormally targeted to C boutons altering their function (VAPB, ALS8; ref. 84). On the other hand, NRG1‐erbB signaling is involved in ALS pathogenesis and erbB4 mutations, which lead to a reduced autophosphorylation of erbB4 protein after NRG1 stimulation and are associated with a hereditary late onset ALS (85).…”

Localization and dynamic changes of neuregulin‐1 at C‐type synaptic boutons in association with motor neuron injury and repair

“…MN subtype-specific differences in vulnerability during disease conditions are driven by endogenous neuroprotective mechanisms linked to their synaptic activity and excitability, including those related to C-boutons. Several C-bouton-associated proteins are directly linked to ALS, as demonstrated for S1R (31)(32)(33) and vesicle-associated membrane protein B and C (34). In addition, a mutation in the ErbB4 receptor has been identified as a genetic cause of ALS (35), suggesting a role of impaired NRG1 signaling in ALS pathophysiology.…”