Studies of Motoneuorn Death-Insight into SMAs and ALS

Wake Forest University Health Sciences, Winston-Salem NC

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Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Neuronal death is a prominent feature of the developing and pathological central nervous system (CNS). During the past decade work from this investigator and many others has provided valuable information outlining several of the key features of neuronal death. Using chick spinal motoneurons as our model system, we have taken two approaches to identify biochemical and molecular mechanisms underlying motoneuron death resulting from insufficient trophic support. In the first approach, we have investigated if factors identified to have a role in nonneuronal deaths are also involved in motoneuron death. To this end, we identified a translocation of the pro-apoptotic molecule Bax from location in cytoplasm to organelle membrane (mitochondria and nuclear) coincident with the cells commitment to death. Following this event, cytochrome c is released from mitochondria and specific caspases are activated. In the second approach, we performed a subtractive hybridization screen to specifically identify messages that are differentially expressed when motoneurons are committed to cell death. With this approach we found that the amyloid precursor protein (APP) has increased expression in motoneurons deprived of trophic support as compared to healthy counterparts supplied with support. Surprisingly, we identified that APP is a substrate of for caspases and that this interaction may actually promote the neurons commitment to death. The goals of the experiments in this competing renewal application are two fold. First, many of the events that we have identified during the previous period are associated with the execution phase of cell death. We will extend our studies to identify those events that link insult (e.g., loss of trophic support) with the cell's apparent commitment to the death cascade. In the second aim, experiments are plan to examine how neurons respond to the stress of trophic factor deprivation by exploring the roles of exogenous and endogenous Hsps, ubiquitin and the proteasome pathways have in promoting death in the absence of trophic support. Results of these experiments will provide information regarding how motoneurons respond to adverse changes in their environment. These type of data may provide novel insight as to why this neuronal population is susceptible to destruction in amyotrophic lateral Sclerosis (ALS) and the spinal muscular atrophies (SMAs).