Grant: Fellowship - Priority Announcement: Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease, is an adult-onset neurodegenerative disease caused by the progressive loss of motor neurons from the brain and spinal cord. The disease starts as a mild muscle weakness that progresses to complete paralysis and death, usually within 2-5 years from diagnosis. There is no cure or effective treatment. Mutations in a gene called TAR DNA-binding protein (TDP-43) are associated with both familial and sporadic ALS, suggesting that these mutations could be a cause of this disease. Moreover, TDP-43 is also found in the motor neuron inclusions characteristic of ALS. The aim of this project is to understand how TDP-43 is toxic to motor neurons and this will be achieved by: 1) Deleting endogenous mouse TDP-43 in motor neurons; 2) Over-expressing mutant human TDP-43 in mice that are null for TDP-43; 3) Modulating TDP-43 expression in primary motor neuron cultures. With this investigation we hope to develop new mouse models for ALS that will provide fresh insights into the disease mechanism and lead to the design of effective therapeutics.