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Krasnow Institute > Monday Seminars > Abstracts Investigations of the Role of Alpha-Synuclein in the Pathogenesis of Parkinson's Disease Catherine Bennett In 1997, the neuron-specific protein a-synuclein was found to be mutated in a small number of Greek and Italian families with autosomal dominant PD. Soon after, a-synuclein was found to be the major component of Lewy bodies in sporadic PD. A fragment of this protein had been identified in the core of amyloid plaques in 1993. Thus, this protein has become a major focus of interest for researchers interested in neurodegenerative diseases. EM studies of hippocampal CA3 suggested that a-synuclein was exclusively localized to the presynaptic terminal. That finding has been accepted to be generally true for all brain regions. We too find a complete absence of a-synuclein in cell soma in many brain regions, including all of HC, all of striatum and most of cortex. However, the soma of the substantia nigra pars compacta, VTA, and layers 5 and 6 of SS and motor frontoparietal cortex and cingulate cortex are a-synuclein positive. We find a remarkable overlap between regions with a-synuclein in the cell bodies of neurons and the regions that are vulnerable to Lewy bodies in various Lewy body diseases. Marateaus and Scheller, early researchers who characterized a-synuclein before its role in neurodegenerative diseases was discovered, found a strong correspondence between the brain distribution of a-synuclein and PI-linked muscarinic receptors. We have investigated the effect of carbachol stimulation in SY5Y cells, a human neuroblastoma cell line that expresses dopamine, a-synuclein and M1/M3 receptors, and found that muscarinic stimulation induces a translocation of a-synuclein from the plasma membrane to cytosol (probably a light vesicular fraction in cytosol). I have hypothesized that a-synuclein is a mediator of ligand-stimulated muscarinic receptor endocytosis. We are in the process of further testing this hypothesis.
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