Derek Narendra, M.D., Ph.D.
Lasker Clinical Research Scholar
Inherited Movement Disorders Unit
Building 35, Room 2A215
35 Convent Drive
Bethesda, MD 20814
Our group studies inherited movement disorders with a focus on the genetics and molecular pathogenesis of Early Onset Parkinson's Disease (EOPD) (onset at 50 years or before). Whereas idiopathic Parkinson's disease is typically sporadic, EOPD is frequently caused by mutation(s) in a single gene. Many of the genes responsible for EOPD have been identified. The relationship among these genes in the molecular pathogenesis of Parkinson's disease, however, remains ill-defined. We recently discovered that two of these genes, Parkin and PINK1, function in a novel mitochondrial quality control pathway in which impaired mitochondria are targeted for lysosomal degradation by mitophagy (a selective form of macroautophagy). Interestingly, two other genes causing EOPD, DJ-1 and the recently identified CHCHD2, share with Parkin and PINK1 a role in mitochondrial biology, suggesting commonalities in pathogenesis. To characterize the molecular pathogenesis of EOPD, we use a combination of novel genetic tools, advanced imaging methods like super-resolution microscopy, quantitative proteomics, and biochemical studies in cellular and mouse models. Additionally, we are collecting DNA samples and fibroblasts from patients with EOPD to better assess the contribution of known genes to the risk of EOPD and to uncover new causes of EOPD, using exome sequencing. It is our hope that these studies will ultimately clarify the molecular pathogenesis of Parkinson's disease and guide the development of disease-modifying therapy.
Dr. Narendra received his B.A. from Columbia University in 2002, Ph.D. from University of Cambridge in 2012, and M.D. from the University of Michigan in 2012. During his graduate research with mentors Dr. Richard Youle and Professor Sir John Walker, he identified a novel mitophagy pathway involving the coordinated activities of Parkin and PINK1, mutations in which are the leading cause of Early Onset Parkinson's Disease. He completed the Brigham and Women's Hospital & Massachusetts General Hospital Harvard Neurology Residency Program in 2016 with additional fellowship training in movement disorders at the University of Pennsylvania. In 2017, Dr. Narendra received the McFarland Transition to Independence Award for Neurologist-Scientists and joined the NINDS as an Assistant Clinical Investigator within the Neurogenetics Branch (NINDS). His laboratory focuses on the molecular pathogenesis of Early Onset Parkinson's Disease.
Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol. 2008;183(5):795-803.
Huang X, Wu BP, Nguyen D, Liu YT, Marani M, Hench J, Bénit P, Kozjak-Pavlovic V, Rustin P, Frank S, Narendra DP. CHCHD2 accumulates in distressed mitochondria and facilitates oligomerization of CHCHD10. Hum Mol Genet. 2018;27(22):3881-3900.
Liu YT, Huang X, Nguyen D, Shammas MK, Wu BP, Dombi E, Springer DA, Poulton J, Sekine S, Narendra DP. Loss of CHCHD2 and CHCHD10 activates OMA1 peptidase to disrupt mitochondrial cristae phenocopying patient mutations. Hum Mol Genet. 2020;29(9):1547-1567.
Narendra DP, Isonaka R, Nguyen D, Schindler AB, Kokkinis AD, Ehrlich D, Bardakjian TM, Goldstein DS, Liang TW, Gonzalez-Alegre P. Peripheral synucleinopathy in a DJ1 patient with Parkinson disease, cataracts, and hearing loss. Neurology. 2019;92(23):1113-1115.
Narendra DP, Guillermier C, Gyngard F, Huang X, Ward ME, Steinhauser ML. Coupling APEX labeling to imaging mass spectrometry of single organelles reveals heterogeneity in lysosomal protein turnover. J Cell Biol. 2020;219(1).
Related Scientific Focus Areas
Genetics and Genomics
Molecular Biology and Biochemistry
This page was last updated on February 17th, 2021