Grant: CIHR Fellowship

Mitochondria are dynamic organelles that are actively transported within cells and neurons. Maintenance of optimal function and transport is essential for the cell. Mitochondria generate most of the cell supply of energy. Although most of DNA is contained in the cell nucleus, the mitochondrion has its own genome. It encodes 37 genes and its proteome is dynamically regulated. Its central role in cell metabolism, damage and dysfunction is an important factor in a wide range of diseases that often present as neurological disorders, but can manifest as myopathy, diabetes, multiple endocrinopathy, or other multi-system disorders. Recently, many nuclear gene defects were shown to lead to mitochondrial dysfunction. This is the case in Friedreich's ataxia, hereditary spastic paraplegia, and the autosomal recessive spastique ataxia with leukodystrophy (ARSAL). Other diseases not directly linked to mitochondrial enzymes may feature mitochondrial dysfunction; schizophrenia, bipolar disorder, dementia, Alzheimer, Parkinson, epilepsy, stroke, cardiovascular disease, retinitis pigmentosa, diabetes mellitus, amyotrophic lateral sclerosis. Their common link is cellular damage causing oxidative stress and the accumulation of reactive oxygen species. A very recent field has emerged from the stem cell research; the generation of pluripotent stem cells (iPS) from individual patient fibroblasts that would enable the large-scale production of cell types affected by the patient's disease. It is suggested that these cells could be used for disease modeling. In this application, we propose to use skin fibroblast from patients affected by ARSAL to reprogram the cells to a pluripotent state, similar to embryonic stem cells. These cells will then used as a cellular model of the disease for a better understanding of the pathogenesis of an autosomal disease caused by mitochondrial dysfunction. It is believed that iPS cells could potentially be used for cell therapy.