Research in the laboratory of Pamela J. McLean, Ph.D., focuses on understanding the cellular and molecular mechanisms underlying neurodegeneration in Parkinson's disease, dementia with Lewy bodies and related neurodegenerative disorders.
In particular, her research group studies the role of alpha-synuclein, a protein that misfolds and aggregates in the brain regions that are critically involved in these diseases.
Dr. McLean's lab has developed many cell-based models to facilitate their studies of alpha-synuclein. In these models, Dr. McLean's lab is able to induce the improper folding and aggregation of the alpha-synuclein protein to mimic the disease process. These provide powerful models to then study the pathways involved in alpha-synuclein aggregation and toxicity in cells, as well as explore ways to remove the abnormal protein and protect the cells.
As well as cell-based models, Dr. McLean's lab uses animal models and advanced microscopy imaging techniques to study alpha-synuclein misfolding.
- Alpha-synuclein transmission. Although alpha-synuclein has traditionally been thought to exert its detrimental effects inside cells, it is now known that alpha-synuclein can be released from cells and can be transmitted to neighboring cells. These findings have precipitated new hypotheses in the fields of Parkinson's disease and Lewy body disease research that suggests that alpha-synuclein transmission from cell to cell may be responsible for the progression of the disease to different areas of the brain. Dr. McLean's lab is currently focusing research projects in this exciting area.
- Molecular chaperone proteins. Molecular chaperone proteins are used by cells to promote correct protein folding or to target misfolded proteins for degradation. Dr. McLean's lab is currently investigating the role of chaperone proteins on alpha-synuclein-induced toxicity, aggregation and clearance, which includes studies in collaboration with Pfizer to investigate the effect of novel inhibitors that alter levels of molecular chaperones in the brain for their ability to stop alpha-synuclein toxicity and aggregation.
- Protein degradation pathways. The dysfunction of protein degradation pathways has also been implicated to play a role in Parkinson's disease and related disorders. Dr. McLean's lab is pursuing studies aimed at investigating the role of both the autophagy and the proteasomal degradation pathways in Parkinson's disease.
- Presenilin-1. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease may have many molecular pathways in common besides protein misfolding and aggregation. Dr. McLean's lab is currently investigating the role of one particular protein, the Alzheimer's disease-related presenilin-1, in Parkinson's disease and related synucleinopathies.
Significance to patient care
Ultimately, the goal of Dr. McLean's lab is to translate its research findings into new therapies for the many patients who suffer from these devastating diseases.
In continued efforts toward this goal, Dr. McLean's lab has established a collaboration with the Sanford-Burnham Medical Research Institute drug screening facility in Orlando, Fla. Working closely together, Dr. McLean's lab hopes to be able to take its cell models and use them to screen for chemical compounds that can prevent the detrimental effects of alpha-synuclein. Identification of effective compounds could lead to promising new therapies.