Protective Mechanisms Against Apoptic Neurodegeneration in the Substantia Nigra.

摘要

Our goal is to understand mechanisms by which neurotoxicity destroys cells in the substantia nigra. Our hypothesis is that c-JUN kinases (JNK) which can contribute to neuronal death mediate neurodegeneration in the substantia nigra after exposure to MPTP or excitotoxicity. Results in year 3 indicated that mice lacking JNK 1 or JNK 3 lack neuroprotection against MPTP neurotoxicity in the substantia nigra and excitotoxicity in striatal neuronal cultures. Results support a role for JNK proximal to mitochondrial initiation of apoptosis and overlapping function of JNK isoforms. Furthermore, in another model of neuronal apoptosis p38 and not JNK serves as a target for MAP kinase dependent apoptosis. Additional studies indicate that neuronal apoptotic mechanisms can lead to increased aggregation of proteins in selected neurodegenerative diseases. Preliminary studies on stem cell transplantation were extended to show that knockout of an immune related gene improves survival and integration of stem cells in substantia nigra. Our studies offer a revised signaling system for neuronal apoptosis and new approach to improve survival of bone-marrow derived stem cells in damaged brain.