Experiments described in this proposal are aimed at understanding the molecular mechanisms underlying the development and resistance to neurodegeneration of the specific motor pools. Motor neurons innervating pelvic muscles are clustered in the Onuf s nucleus in the sacral spinal cord. This group of motor neurons is selectively spared from degeneration in Amyotrophic Lateral Sclerosis (ALS). I intend to understand how genes specifically expressed in the Onuf's nucleus motor neurons direct their development and contribute to their disease-resistance. I already found one gene that is specifically expressed in a subset of ALS-resistant motor neurons. POU4F3, also known as BrnSc, is expressed in the ischiocavernosus motor pool from late embryonic to early postnatal stages. This is the most highly restricted expression for any motor pool marker reported to date.
Specific Aim 1 will focus on the molecular basis of ALS-resistance of Onuf's nucleus motor pools by (1) determining the extent of preservation of pelvic muscle-innervating motor pools in mutant SOD1 mouse models of familial ALS (2) Identifying potential disease resistance genes selectively enriched in pelvic motor pools and ALS-resistant oculomotor nucleus using comparative microarray analysis, and by (3) assessing neuroprotective function of these genes in the in vitro models of motor neuron degeneration relevant to ALS.
Specific Aim 2 will focus on the role of POU4F3 in the development of the ischiocavernosus motor pool by (1) performing detailed phenotypic analysis of POU4F3 mutant animals during various developmental stages and (2) identifying potential upstream factors and downstream effectors of POU4F3 genetic pathway.
ALS is a uniformly fatal condition for which there is currently no available therapeutics. Uncovering mechanisms that underlie disease resistance of certain motor neurons will provide novel insights into processes of motor neuron degeneration taking place in ALS. Discovery of molecules with neuroprotective potential for ALS motor neurons will pave the way for the development of new strategies for therapy design, providing hope to victims of this devastating disease.
