Clinical Neuroscience and Neurogenetics
Dr. Chris Grunseich is a Lasker Clinical Research Scholar and Investigator, and head of the Inherited Neuromuscular Diseases Unit, NINDS. He is a physician-scientist specializing in inherited neuromuscular diseases at the NIH Campus in Bethesda, MD. His lab focuses on studying markers of muscle and motor neuron pathology that can be used for detecting disease progression and evaluating efficacy in clinical studies. Dr. Christopher Grunseich completed his undergraduate studies at Brown University, and went on to receive his M.D. from SUNY Stony Brook School of Medicine in 2006. While at SUNY Stony Brook he completed an HHMI research fellowship year working in the laboratory of Dr. Gail Mandel. He then completed medical internship at St. Vincent’s Hospital, and his residency training in neurology at Georgetown University. He joined Dr. Kenneth Fischbeck’s research group as a neurogenetics fellow, and became a Staff Clinician in 2016, a Lasker Clinical Research Scholar in 2024 and is currently a Tenure Track Investigator. Dr. Grunseich is board certified in Neurology and oversees an active clinical research program at the NIH Clinical Center.
Research Interests:
The Inherited Neuromuscular Diseases Unit, led by Dr. Grunseich, is part of the Neurogenetics Branch of NINDS. The lab is a translational science lab working on developing treatments for patients with inherited forms of neuromuscular disease. Dr. Grunseich and his research group are interested in studying genetic forms of motor neuron diseases, developing clinical and molecular markers of disease progression, and performing clinical studies to evaluate candidate therapies in motor neuron disease patients. They have recently performed clinical studies of exercise and an IGF-1 pathway stimulating agent in patients with spinal and bulbar muscular atrophy (SBMA) and have used the MRI measurement of thigh muscle volume to evaluate efficacy.
The group uses patient derived cell models to better understand the biology of motor neuron diseases such as SBMA and inherited forms of ALS. To generate sufficient numbers of cells for their studies, they have developed a system to introduce inducible hNIL transcription factor (NGN2, ISL1, and LHX3) transgene cassettes into the patient- derived stem cells, which facilitates their rapid and efficient differentiation to motor neurons. These cells can then be used to better understand the disease and evaluate candidate therapies.
One of the disruptions in RNA biology that they have characterized in the patient cells is a dysregulation of R-loops. R-loops form as newly transcribed RNA hybridizes to its DNA template to form an RNA-DNA hybrid. In studying amyotrophic lateral sclerosis due to senataxin mutation, ALS4, the group discovered that patients have defects in RNA processing from dysregulation of R-loops. They characterize the distribution of R-loops in different cell types and show how the senataxin mutation results in a gain of function in senataxin’s ability to resolve R-loops within patient cells.
Lab Members:
- George Harmison, B.S., M.S. - Biochemist and Lab Manager
- Abdullah AlQahtani, M.D., M.P.H. - Clinical Fellow
- Andrew Nguyen, B.S. - Postbac IRTA
- Marie Ezuma-Ngwu, B.S. - Postbac IRTA
- Jahan Misra, B.S. - Postbac IRTA
Selected Publications
- Grunseich C, Wang IX, Watts JA, Guber RD, Burdick JT, Zhu Z, Bruzel A, Lanman T, Chen K, Schindler AB, Edwards N, Ray-Chaudhury A, Yao J, Lehky T, Piszczek G, Crain B, Fischbeck KH, Cheung VG. Senataxin mutation reveals how R-loops promote transcription by blocking DNA methylation at gene promoters. Mol Cell 2018;24:313-325.
- Guber RD, Kokkinis AD, Schindler AB, Bendixen RM, Heatwole CR, Fischbeck KH, Grunseich C. Patient-identified impact of symptoms in spinal and bulbar muscular atrophy. Muscle Nerve 2018;57:40-44.
- Grunseich C, Patankar A, Amaya J, Watts JA, Li D, Ramirez P, Schindler AB, Fischbeck KH, Cheung VG. Clinical and molecular aspects of senataxin mutations in amyotrophic lateral sclerosis 4. Ann Neurol 2020;87:547-555.
- Pourshafie N, Masati E, Lopez A, Bunker E, Snyder A, Edwards NA, Winkelsas AM, Fischbeck KH, Grunseich C. Altered SYNJ2BP-mediated mitochondrial -ER contacts in motor neuron disease. Neurobiol Dis 2022;172:105832.
- Alqahtani A, Kokkinis A, Zizzi C, Dilek N, Fischbeck KH, Heatwole CR, Grunseich C. Patient-reported impact of symptoms in spinal and bulbar muscular atrophy. Neurology Clinical Practice 2023.