Protective Mechanisms Against Apoptic Neurodegeneration in the Substantia Nigra
Abstract
The goal in this proposal is to understand mechanisms by which neurotoxicity destroys cells in the substantia nigra Our hypothesis is that c-JUN kinases (JNK), which is a set of enzymes known to participate in death of neurons, mediates neurodegeneration in the substantia nigra after exposure to MPTP or glutamate excitotoxicity. Spurred by the DoD meeting in Potomac, 2001, I have extended our research in Parkinson's disease to include new strategies to improve survival of stem cells in mammalian brain. We also modified our protocol for MPTP neurotoxicity after ad hoc reviews of our data at the DoD meeting. Results in year 3 of our proposal indicated that mice lacking JNK 1 or JNK 3 lack neuroprotection against MPTP neurotoxicity, as measured by loss of tyrosine hydroxylase labeled neurons. The changes in protocol made our results more robust and reproducible, compared to the former protocol. Results favored an apoptotic pathway where JNK activity is proximal to mitochondrial initiation of apoptosis. Our group reported a role for p38 and not JNK as a target of MAP kinase apoptosis after nerve growth factor withdrawal. Mutant Huntington gene causes striatal neurons to have increased responsiveness to NMDA receptor activation. Caspase 3, a key enzyme for transducing apoptotic signals, cleaves mutant Huntington in cells transfected with Huntington cDNA and in Huntington's disease brain. Pilot results show that intravenously injected, bone-marrow derived stem cells form neuron-like cells in mice genetically engineered to accept transplanted tissues. In year 4, we will submit manuscripts on neuroprotection of JNK knockout mice for MPTP, the role of AP-1 transcription in this paradigm, and neurotoxicity of quinolinic acid in JNK knockout and Huntington's disease mouse models. We will initiate studies to improve stem cell transplantation in mouse brains after neurotoxic lesions.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2001
- Accession Number
- ADA400481
Entities
People
- Neil Aronin
Organizations
- University of Massachusetts