Grant: Operating Grant - PA: INMHA (bridge funding)

Amyotrophic lateral sclerosis (ALS) is commonly referred to as Lou Gehrig disease, the NY Yankee baseball player diagnosed with the disorder. It is caused by death of motor neurones, resulting in loss of voluntary muscle control and paralysis. One of the 11 known genetic mutations linked to ALS, designated ALS8, is caused by a mutation in the VAPB gene. In this study, we found that this mutant protein also causes a nuclear envelope defect. The nuclear envelope serves as a physical barrier separating genes in the nucleus from the cytoplasm. Thousands of nuclear pores in the nuclear envelope act as gatekeepers in regulating movement of molecules in and out of the nucleus. Nuclear pores are long-lived structures with a very low rate of replenishment in non-dividing cells such as neurones. Mutant VAPB traps proteins that make up the nuclear pores in the cytoplasm, cutting off this supply route to the nuclear envelope. This means that normal ageing associated deterioration of or damage to nuclear pores are not readily replaced in ALS8 patients. Progressive deterioration of nuclear pores leads to a leaky envelope, and mixing of nuclear and cytoplasmic proteins. The goal of this study is to understand how this mutant protein affects the formation of the nuclear envelope and how these membrane defects can be prevented and resolved.