Massachusetts General Hospital

Pamela J. McLean, PhD

• Assistant Professor of Neurology Harvard Medical School

 

 

 

 

Research Description

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.

Research interests	Cellular and molecular mechanisms underlying neurodegeneration
Research Techniques	Advanced microscopy
Diseases studied	Parkinson's disease, dementia with Lewy bodies
Selected publications	Outeiro TF, Kontopoulos E, Altman S, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet J-C, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, and Kazantsev A. Sirtuin 2 Inhibitors Rescue Alpha-Synuclein-Mediated Toxicity in Models of Parkinson’s Disease. Science 2007a In Press J.L. St. Martin, J. Klucken, T.F. Outeiro, P. Nguyen, C. Keller-McGandy, I. Cantuti-Castelvetri, T.N. Grammatopoulos, D.G. Standaert, B.T. Hyman, and P.J. McLean. Dopaminergic neuron loss and upregulation of chaperone protein mRNA induced by targeted overexpression of alpha-synuclein in mouse substantia nigra. J. Neurochem. 2007 100(6) 1449-1457 Bodner R, Outeiro TF, Altman S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, and Kazantsev AG. A novel approach to therapeutic interventions for Huntington’s and Parkinson’s diseases. Proc Natl Acad Sci 2006, 103(11) 4246-4251. Outeiro TF, Klucken J, Strathearn KE, Liu F, Nguyen P, Rochet J-C, Hyman BT, and McLean PJ. Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation Biochem. Biophys. Res. Comm. 2006 351(3) 631-638. Klucken J, Outeiro TF, Nguyen P, McLean PJ, and Hyman BT. Detection of novel intracellular a-synuclein oligomeric species by fluorescence lifetime imaging. FASEB J. 2006; 20(12):2050-2057.
NCBI PubMed link	NCBI PubMed Publications
NIH biosketch	Pamela J. McLean, PhD
E-mail address	pmclean@partners.org
Lab mailing address	MassGeneral Institute for Neurodegenerative Disease 114 16th Street Charlestown, MA 02129
Lab telephone	617-726-1263
Lab, institute or center websites	www.mghmind.org