Clearance of membrane aggregates in mutant ALS8

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A single amino acid mutation, proline residue at position 56 substituted by serine (P56S), in a previously identified gene named VAPB causes late-onset, autosomal dominant form of Amyotrophic Lateral Sclerosis (ALS8). VAPB is a protein anchored to the membrane of the endoplasmic reticulum (ER), a cellular network of membranes that is the entry point for secretory and membrane proteins. The ER has a quality control feature to ensure that proteins are correctly folded before they can leave the ER en route to their final destinations. Expression of VAPB-P56S disrupts this quality control feature and slows down the exit of proteins from the ER. This creates a protein traffic jam that eventually causes aggregation and stress to the ER. Cells have an adaptive process known as the unfolded protein response or UPR to counteract ER stress. UPR is designed to reduce the effect of increased protein load by (1) expanding the membrane capacity of the ER to accommodate the increased load; (2) by promoting the degradation of unfolded proteins; and (3) by temporarily shutting down new protein synthesis to reduce the amount of proteins entering the ER. However, if these countermeasures fail to relieve the stress, genes leading to cell death are then activated to eliminate the affected cell. We have discovered that a short peptide sequence known as the FFAT motif (two phenylalanines in an acidic tract) can change the activity of VAPB. It rescued the defect caused by the P56S mutation, so that proteins can now effectively leave the ER thereby relieving stress to the ER. This study will determine how the ALS8 mutation changes the UPR, and how FFAT resolves the ER membrane aggregates. It will explore whether this approach can be applied to other aggregate-prone neurodegenerative diseases such as Huntington's and Parkinson's Diseases.