Depletion of Mitochondrial S-Nitrosothiols in ALS

Univ Of Massachusetts Med Sch Worcester, Worcester MA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): There is increasing evidence that mitochondrial dysfunction contributes to amyotrophic lateral sclerosis (ALS) pathogenesis. However the causes of mitochondrial dysfunction in ALS are not known. We hypothesize that familial ALS-associated SOD1 mutants aberrantly deplete S-nitrosothiols (SNOs) in mitochondria leading to mitochondrial degeneration and motor neuron death. S-nitrosothiols are peptides and proteins that have an NO group attached to a cysteine residue. Peptide SNOs are potent antioxidants and neuroprotective. S-nitrosylation of critical cysteine residues on proteins is emerging as a mechanism of signal transduction regulation. Therefore aberrant depletion of mitochondrial SNOs is likely to be a toxic gain-of-function of SOD1 mutants. This is a novel testable working hypothesis in a virtually unexplored area in the ALS field. In support of our hypothesis, our preliminary data indicate that peptide and protein SNOs are located primarily in the mitochondria of cell lines expressing wild-type SOD1. Moreover, SNO levels are significantly decreased in the mitochondria of cells expressing SOD1 mutants. In specific aim 1 of the proposed studies we will extend our preliminary studies in cell lines to an in vivo animal model and determine if mitochondrial SNO levels are decreased in the spinal cord of mutant SOD1 transgenic mice before or at the time of onset of muscle weakness. In specific aim 2 we will determine if restoration of mitochondrial SNO levels improves mitochondrial function and the viability of cells expressing mutant SOD1. If we confirm our hypothesis, then in future studies we will determine if SNO donor compounds improve the survival of mutant SOD1 transgenic mice. Our long term goal is to determine if SNO donor compounds (which have been used for decades in the treatment of coronary artery disease with limited toxicity) have therapeutic efficacy in patients with ALS.