Disruption of nucleocytoplasmic transport in SOD1 ALS

Abstract in layman terms Application # 2017118 Disruption of nucleocytoplasmic transport in SOD1 ALS Adrian Israelson, Ben-Gurion University of the Negev, Israel Clotilde Lagier-Tourenne, MGH and Harvard Medical School, Boston, MA Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons, resulting in progressive muscle weakness and inevitable paralysis. This devastating disease is unfortunately common, as it is the cause of death in one per 1,000 people and is almost always fatal within one to five years. There is currently no effective treatment for ALS. Most of ALS cases are sporadic, but 10% are inherited in a dominant manner.

Twenty percent of these familial cases have been attributed to mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1).

It has been 24 years since the finding that mutant SOD1 causes ALS. However, the mechanisms leading to neuronal death are still not well understood. A compelling pathway through which these mutations result in ALS is through misfolding of the SOD1 protein and the damages caused by accumulation of abnormal protein to intracellular biological mechanisms.

One of these mechanisms, which was recently shown to be affected in other ALS models and neurological diseases, is the transport of proteins and RNA between two cellular compartments, the nucleus and the cytoplasm. This function is crucial for the proper function of the cell and disruption of this process may result in toxicity and cell death. How and why this disruption occurs, is still unknown.

We will determine how misfolded SOD1 accumulation affects the nucleocytoplasmic transport in SOD1-related ALS and we will test the therapeutic potential of a gene delivery approach to reverse these toxic effects. Understanding how motor neurons die, and the pathways to which they are especially vulnerable, will provide valuable insight needed for development of therapies that either prevent or slow the degenerative process in neurodegenerative diseases.