Clemens R. Scherzer, M.D. is Assistant Professor of Neurology at Harvard Medical School, Associate Neurologist at Brigham and Women’s Hospital, and directs the Laboratory for Neurogenomics. He is the Coordinating Principal Investigator of the Global Parkinson’s Disease Gene Expression Consortium (GPEX). He received the Paul B. Beeson Award of the American Federation for Aging Research and the National Institute on Aging, and a Dr. George Cotzias Memorial Award of the American Parkinson’s Disease Association. He completed neurology residency at Emory University and fellowship training in movement disorders and in genomics at Massachusetts General Hospital and Harvard Medical School. In his clinical practice he works as a movement disorders specialist at Brigham and Women’s Hospital and Massachusetts General Hospital, and is the Co-Director of the Harvard NeuroDiscovery Biomarker Study.
Genomic and genetic analysis of Parkinson’s disease and other neurodegenerative diseases.
We apply genomic approaches to the detection, characterization, and treatment of Parkinson’s disease (PD). Our leading hypothesis is that genome-wide expression analysis can define biomarkers, modifier and susceptibility genes for complex neurodegenerative diseases by detecting allele-specific gene expression and differential transcription in response to disease proteins. We identify and test candidate genes in clinical studies and cellular and animal models.
Increased α-synuclein gene (SNCA) dosage due to locus multiplication causes autosomal dominant Parkinson’s disease (PD). Variation in SNCA expression may be critical in common, genetically complex PD but the underlying regulatory mechanism is unknown. We pinpointed GATA factors as the transcription factors of SNCA by deconvoluting the co-expression patterns of thousands of genes across 113 human specimens. GATA-1 and GATA-2 specifically bind to a conserved binding motif in the SNCA locus and directly activate SNCA transcription (Scherzer et al., Proceedings of the National Academy of Sciences U.S.A., 2008). Future studies will analyze the pathobiological and therapeutic implications of this finding.
In Alzheimer’s disease (AD), our original discovery of abnormally low message levels of the neuronal sorting receptor SORL1/LR11 in patients with AD (Scherzer et al., Archives of Neurology, 2004) started a new field of investigation. SORL1/LR11 directs Amyloid-β trafficking and is now linked to genetic susceptibility for AD.
In the substantia nigra of individuals affected by PD and in PD models, we found profound expression changes of genes involved in cellular quality control and energy metabolism (Scherzer et al., Human Molecular Genetics, 2003; Hauser et al., Archives of Neurology, 2005). Degeneration of dopamine neurons is the tip of the iceberg of PD. Related biochemical processes are perturbed in extranigral tissues of patients with PD. To systematically interrogate the molecular processes perturbed in cellular blood of patients with early-stage PD, we perform transcriptome-wide scans (Scherzer et al., Proceedings of the National Academy of Sciences U.S.A., 2007; Hennecke & Scherzer, Biomarkers in Medicine, 2008; Scherzer, Neurobiology of Disease, in preparation). Leads are discovered and developed into clinically useful blood tests for diagnosing, predicting and tracking disease progression in our several large, well-designed clinical biomarker studies. These includes the unique, two-year, longitudinal, Harvard NeuroDiscovery Biomarker Study of 2,000 patients and controls.
The laboratory is funded by the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Michael J. Fox Foundation, the American Federation for Aging Research, and the Harvard NeuroDiscovery Center.