Grant: Fellowship - Priority Announcement: Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease characterized by degeneration of motor neurons in the motor cortex, brainstem and spinal cord that control muscle movement. The majority of ALS cases occur sporadically (SALS), with only 5-10% having a family history (FALS). Whereas 60-80% of FALS cases are explained by mutations in the germ line, the impact of genetics in SALS remains unclear. The genetic mutations linked to ALS have been discovered by analyzing DNA isolated from blood, not from tissues most affected by the disease. It is important to recognize that genetic mutations can arise not only in eggs and sperm, but during cell division at various stages of development, as for example, leading to cancer. These so called somatic mutations will not be present in all tissues. I hypothesize that somatic mutations generated during the development of embryonic spinal cord could later trigger the development of SALS. I will screen spinal cords of individuals who have succumbed to SALS using highly sensitive and innovative next generation sequencing approaches. To maximize chances of detecting low frequency mutations, I will focus analysis on the region of the spinal cord first affected in the individual, as indicated by the deficits first reported for diagnosis. Collection of spinal cords and the clinical documentation is made possible through unique collaborations with neurologists and neuropathologists at multiple Canadian ALS clinics. Identifying somatic mutations associated with SALS would have an enormous impact on our understanding of the pathophysiology of ALS - starting from the validation of the two phase hypothesis of ALS (focal initiation followed by spread of disease), and changing our approaches to modeling the disease experimentally and finding ways to prevent or significantly slow its progression.