Molecular Mechanisms Underlying Motor Neuron Degeneration

Our research interests focus on mechanisms underlying pathogenesis of motor neuron diseases including early-onset spinal muscular atrophy (SMA) and late-onset Amyotrophic Lateral Sclerosis (ALS). Using a combination of molecular biology, electrophysiology, gene profiling, and genetic manipulation we are investigating molecular events related to motor neuron degeneration in cell cultures and mouse models. Our goal is to identify molecular targets for early detection and prevention of motor neuron diseases.

N-methyl-D-aspartate (NMDA) receptors are a subtype of glutamate receptors that play a critical role in the development and maintenance of the central nervous system, including the motor system. We have characterized the subunit composition of NMDA receptors in the lower motor neurons, suggesting these receptors may mediate excitotoxicity in the early stage of motor neuron development. We have recently cloned and characterized a novel NMDA receptor subunit, NR3B, that is highly expressed in motor neurons. The NR3B knockout mice generated in our laboratory show the phenotype of an early-onset motor neuron disease that results from a specific degeneration of motor neurons in the early postnatal stage. Further analysis along these lines will provide a molecular basis for understanding the role of the NMDA receptor in motor neuron degeneration.

The mechanisms underlying the selective death of motor neurons have not been fully investigated in ALS research. We hypothesize that the expression level of a specific group of genes is modified at various disease stages leading to selective death in ALS-susceptible motor neurons. We have undertaken gene expression profiling experiments using an animal model of ALS, the superoxide dismutase-1 (SOD1) mutant mouse. Our goal is first to identify a group of disease state-specific genes whose expression levels change in the early pre-symptomatic stage. We will then characterize and finally alter the expression level of three selected genes genetically to further delineate the role they play in motor neuron diseases. These studies will lead to a better understanding of molecular processes linked directly to motor neuron death. Most importantly, these genes would be appropriate targets for developing strategies to treat inherited and sporadic forms of ALS.