Grant: Operating Grant

Amyotrophic lateral sclerosis (ALS) is commonly referred to as Lou Gehrig disease. It is caused by premature death of motor neurones that control skeletal muscles. Their death results in in loss of voluntary muscle control and paralysis. Approximately 90% of ALS is sporadic with the remaining 10% classified as familial caused by inheritance of the mutated gene in affected families. A familial form of ALS, designated ALS8, is caused by a mutation in a gene known as VAPB. This mutation resulted in production of a defective mutant VAPB protein. The function of this protein is currently unknown. We found that cells expressing mutant VAPB have a defective nuclear envelope. The nuclear envelope serves as a physical barrier separating genes in the nucleus from the rest of the cell or cytoplasm. Each cell contains ~3,000 nuclear pores in the nuclear envelope that act as gatekeepers regulating movement of molecules in and out of the nucleus (e.g. messenger RNA made in the nucleus are transported out to the cytoplasm to be translated into proteins). Nuclear pores are made up to ~50 different proteins. Most pores are made shortly after a cell divides. Once assembled, pores are extremely long-lived lasting the entire lifespan of a cell. This means that when damaged, pores are not easily replaceable in cells that no longer divide, such as neurones. We found that pore components are pre-assembled in the cytoplasm and these pre-assembled units are guided by VAPB to the nuclear envelope for final assembly into functional pores. Mutant VAPB cuts off this supply route to the nuclear envelope. This leads to progressive deterioration of the pores, a process that is normally associated with ageing but accelerated in ALS8 patients. One of the goals of this study is to understand how damages caused by mutant VAPB can lead to motor neurone death.