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Pamela J. McLean, PhD
Dr. McLean uses genetic and molecular approaches to understand the cellular and molecular mechanisms underlying neurodegeneration in Parkinson's disease, dementia with Lewy bodies and related disorders. In particular, her research group studies the role of a protein called alpha-synuclein, which accumulates in Lewy bodies in the neurons that are prone to die in these diseases.
Dr. McLean’s group has shown that modifications to the carboxy-terminus of alpha-synuclein can lead to protein misfolding and aggregation. Dr. McLean uses advanced microscopy techniques to demonstrate the presence of oligomeric forms of alpha-synuclein in cells and she has shown that alpha-synuclein oligomers assemble in a head-to-tail orientation. Dr. McLean’s studies of alpha-synuclein conformation in vitro suggest that specific factors modulate alpha-synuclein conformation. She postulates that oligomeric forms of alpha-synuclein are causative of neuronal dysfunction, and her group has developed FRET methodologies to see these molecular conformations in cells. Future studies will continue to develop advanced methodologies to facilitate phamacological and gene-based studies to alter the formation or clearance of these misfolded forms of alpha-synuclein.
Dr. McLean has demonstrated that molecular chaperones are dysregulated in Lewy body disease and that they colocalize with alpha-synuclein in Lewy bodies. In addition, her work has demonstrated that alpha-synuclein aggregation and toxicity can be prevented by expressing molecular chaperones such as Hsp70, Hsp40, Hsp27 and CHIP. Her present research projects focus on the role of chaperone proteins on alpha-synuclein induced toxicity, aggregation, and clearance. Previous studies have demonstrated that the antibiotic and Hsp90 inhibitor, geldanamycin, can prevent alpha-synuclein induced cell death and aggregation. Current studies are investigating the effect of novel small molecule aggregation inhibitors and novel Hsp90 inhibitors on alpha-synuclein toxicity and oligomerization. These studies use an in vitro cell culture model of alpha-synuclein aggregation as well as transgenic animal models.
Dr. McLean has established viral vector gene transfer technology in her group. Using targeted overexpression of alpha-synuclein with adeno-associated virus (AAV) she developed a mouse model of Parkinson’s disease that is characterized by neuronal cell death and Parkinson disease-like pathology. Currently, Dr. McLean’s group is using targeted overexpression of alpha-synuclein via AAV8 into rat substantia nigra to study mechanisms of alpha-synuclein induced cell death.
Cellular and molecular mechanisms underlying neurodegeneration
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