MITOCHONDRIAL DYSFUNCTION IN AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic Lateral Sclerosis (ALS) is a severe neurodegenerative disease, wich affects motor neurons leading to progressive paralysis and premature death. The onset of the disease is generally in the fourth and fifth decade with an annual incidence of 1 in 100,000. Patients experience progressive paralysis and they usually die within 5-10 years after the onset of the disease. While most cases are sporadic, about 5-10% are familial (FALS), with approximately 25% associated with mutations in the SOD1 gene on human chromosome 21. This identification of SOD1 mutation, the only disease gene known in FALS, allowed the development of transgenic mouse model to clarify the pathophysiology of the disease. Several experimental evidences have postulated the involvement of mitochondrial DNA (mtDNA) abnormalities in the neurodegeneration observed in ALS. Moreover, defective mitochondrial respiratory chain function has been reported in tissues of patients with ALS, as well in the mouse models. This has suggested a role for abnormal mitochondrial bioenergetic in the progression of the disease. The applicant plans in this project to analyze both cellular (i.e., human fibroblasts and cybrids; murine cultured neuroblastoma cells) and animal models (transgenic mice) to define the role of mitochondrial alterations in the pathogenesis of ALS and and the mechanisms responsible for the motor neuron loss. This might have a potential impact on therapeutic strategies.