| Amyotrophic lateral sclerosis is a neurodegenerative disease that affects motor neurones of the central nervous system leading to the loss of voluntary muscle control. The objective of this study is to characterize the cellular effects of the P56S mutation in the VAPB gene identified in ALS8, and how these might lead to neurodegeneration.;Over-expression ofVAPB-P56S induced formation of expanded endoplasmic reticulum tubules and caused nuclear envelope defects resulting in functional deficits. The mutation inhibited transport of correctly folded membrane proteins from the ER to the Golgi complex and dampened activation of the IRE1 and ATF6 signaling pathways of the unfolded protein response. VAPs interact with lipid binding proteins containing a FFAT motif and co-expression of a FFAT motif resolved the morphological and functional deficits, suggesting that VAPB-P56S might be a gain of toxic function and that the FFAT motif acts as a competitive agonist in counteracting this toxic effect. |
