The central pathologic event in Amyotrophic Lateral Sclerosis (ALS) is the selective degeneration of motor neurons. While most cases (-90%) are sporadic, the familial cases are due to mutations in a variety of different genes such as SOD1 and p150glued. Excessive activation of glutamate receptors (excitotoxicity) is an early triggering event. The death of motor neurons from excitotoxic insult or mutant gene expression can be studied in cell culture using dissociated rodent embryonic spinal cord tissue. Our previous in vitro work demonstrates that excitotoxic motor neuron death only occurs if Brain-derived neuronotrophic factor (BDNF) signaling via TrkB is intact. The phosphatidylinositol 3' kinase (PI3'K) signaling cascade is activated by TrkB and PI3'K signaling is necessary and sufficient for BDNF-induced excitotoxic death of motor neuron. Pharmacological manipulations that inhibit Trk activation can also protect motor neurons from the toxic effects of mutant SOD1 and p150glued. This can be accomplished using proprietary derivatives of K252a (made by Cephalon Pharmaceuticals) or by inhibiting the activation of adenosine A2A receptors.
In specific aim #1 we will examine the alterations in intracellular signaling cascades that follow from administration of these agents. The potential interplay between mutant SOD1 and p150glued and Trk signaling events will also be studied.
In specific aim #2, we will study the in vivo pharmacodynamics of these agents on Trk activation and signaling. This is a prelude to future studies in which we hope to examine the efficacy of these agents in animal models of ALS.
In specific aim #3 we will study the signaling cascades downstream of activated PIS'K (two serine-theonine kinases (PDK1, Akt) and small monomeric GTP'ases of the RhoA and Arf families) to see which is needed to evoke excitotoxic sensitivity of motor neurons. This will define susceptibility-to-toxicity intracellular signaling pathways in motor neurons. Relevance: The proposed work attempts to translate basic science observations into new treatments for ALS. The development of new drug targets for ALS could guide the way for novel therapies for other, more prevalent, neuro-degenerative disorders. ? ? ?
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