The death of motoneurons is a significant event during normal development of the spinal cord, but results in devastating pathologies such as the SMAS and ALS. My laboratory, and others, has investigated the intracellular mechanisms mediating neuronal death. We have identified several events that appear critical for the execution phase of motoneuron cell death, but have learned through these studies that earlier events such as changes in signal transduction may be critical for cellular dysfunction that precedes cell death. One of the signal transduction pathways that we focused on during the previous award was the c-Jun N-terminal kinase (JNK) pathway. Interestingly, the role of the JNK pathway appears to be very complex, with roles in mediating both survival- and death- associated events in motoneurons. Furthermore, intracellular localization of JNK activity may be critical to its function in promoting survival or possibly dictating function. We have also found that activation of JNK in astrocytes following stress contributes to a decrease in their ability to secrete MN survival-promoting factors. In independent studies examining the role for motoneuron death in the G93A SOD1 mouse model of ALS, we found that muscle denervation/motoneuron dysfunction, rather than cell death, appears to mediate symptoms, and that when motoneuron death is inhibited, there is only a modest increase in survival. Considering the roles of JNK in mediating neurite outgrowth, axonal transport and cell death, we believe that additional studies into the role of this pathway will provide essential insight into critical, biological events that regulate motoneuron innervation patterns and cell death during development and in disease. We therefore are proposing to test the following hypotheses: 1. JNK plays specific, yet discrete roles in motoneuron development. 2. JNK plays specific roles in motoneuron response to stressful environmental changes. We are fortunate to have established a collaboration with Thomas Herdegen at the University of Heidlleburg, and he has recently sent us the JNK1, JNK2 and JNK3 knock-out mice. Our previous results, and the availability of these mice, together with our combined expertise places us in an unique situation to examine the role of this specific pathway in motoneuron development and pathology. This information may provide novel insight as to why this neuronal population is specifically susceptible to destruction in ALS and the SMAs. PUBLIC HEALTH RELEVANCE: My laboratory's research focuses on motoneuron survival and death mechanisms. This project outlines experiments to investigate the role of a specific signal transduction pathway that appears to mediate both survival and death associated events, in motoneuron development and response to stressful challenges in the environment. The results of this work will contribute to our understanding of why motoneurons may be susceptible to injury and death in neurodegenerative diseases such as the SMAs and ALS.