Envronment-Sensitive genes in motoneuron degeneration

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DESCRIPTION (provided by applicant): The goal of this project is to identify functional variants of environmentally responsive genes that are biologically relevant to motor neuron degeneration of sporadic amyotrophic lateral sclerosis (SALS) and primary lateral sclerosis (PLS). Considerable progress has been made in inherited motor neuron degeneration where genes such as SOD1 and ALSIN have been discovered and suitable animal models engineered. However etiology of SALS and PLS remains undefined. Both are complex disorders and a genetic and it is widely accepted susceptibility encoded in the genome interacts with environment stressors to produce motor neuron degeneration. These investigators have recently identified two sets of genes of environmentally responsive enzymes that are etiologically relevant to motoneuron degeneration. The PON cluster of genes (PON1, 2 and 3) was associated with SALS and this finding has been validated in four other studies. Mutations in the second gene, CYP7B1, are caused in corticospinal degeneration in a form of hereditary spastic paraplegia (SPG5A). PONs are antioxidant and detoxify pesticides, while CYP7B1 is inhibited by agricultural fungicides. A detailed examination of variations in these genes and in genes related to them by metabolic pathways and coexpression for association to SALS and PLS will be accomplished. Further, their interactions with environmental exposure to pesticides, fungicides and other relevant stressors will also be examined. This is a novel opportunity for a comprehensive study of two etiologically relevant environmentally responsive genes in SALS and PLS. 1000 ALS cases, 400 PLS cases and 1000 matched controls will participate in this study. This investigation will establish genetic and environmental risks, and lead to rational treatment and prevention of disabling fatal disorders of PLS and SALS.