Chief, Section on Molecular Neurogenetics
Medical Genetics Branch
National Human Genome Research Institute of the National Institutes of Health
The central goal of Dr. Sidransky’s research in the Section of Molecular Neurogenetics is to understand and to optimize treatment for a rare single gene disorder, Gaucher disease, and to apply the insights gained towards a better understanding of Parkinson disease, a common complex disorder. As a physician, she uses a translational approach, integrating both clinical and basic science research, utilizing molecular and protein analyses, cellular and animal models, genomic strategies, high-throughput screens, imaging, and patient studies to achieve her goals. Her research resulted in the paradigm-shifting discovery of a link between Gaucher disease and Parkinson disease. Mutations in the gene encoding glucocerebrosidase (GBA1) are now the most common known genetic risk factor for parkinsonism, including both Parkinson disease and other Lewy body disorders, and Dr. Sidransky spearheaded two large international multicenter collaborations definitive establishing this association, published in the New England Journal of Medicine and JAMA Neurology. Her laboratory and clinical team have led ground-breaking work on GBA1-related parkinsonism using patient samples, mouse models and induced pluripotent stem cell lines. They have contributed to a recognition of the role of lysosomal pathways in neurodegenerative disorder and have developed small molecule chaperones that enhance the delivery of glucocerebrosidase to the lysosome and decrease alpha-synuclein levels in neurons. Moreover, they have carefully evaluated patients with both Gaucher disease and parkinsonism,and have longitudinally followed a large cohort of at-risk individuals, performing periodic clinical, imaging and biochemical assessments. Thus, exploring the bases for this association is yielding new insights into the pathogenesis and treatment of both Gaucher disease and Parkinson disease.