Joshua M. Shulman, M.D. Ph.D.
Assistant Professor, Department of Molecular and Human Genetics
Assistant Professor, Department of Neurology, Baylor College of Medicine
Investigator, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital
A.B., Harvard College, 1997
Ph.D., University of Cambridge, 2000
M.D., Harvard Medical School, 2005
Resident in Neurology, Brigham & Women’s Hospital, Massachusetts General Hospital, 2009
Movement Disorders Fellow, Brigham & Women’s Hospital, Massachusetts General Hospital, 2010
Recent advances have made the discovery of genetic susceptibility loci for complex human phenotypes a reality, including nervous system disorders. The critical next step will be to definitively identify the responsible genes and understand their functions in both health and disease. Our research integrates genetic investigation in human subjects and model organisms, with the goal of understanding brain function and aging, and improving the treatment of neurologic disease. We focus on Alzheimer’s disease and Parkinson’s disease, two incurable neurodegenerative disorders and experimental paradigms for the age-dependent failure of brain cognitive and motor control in humans.
Human Genetics: The clinical manifestation of neurodegenerative disease is the culmination of a multi-tiered pathogenic cascade that evolves over decades—understanding how genetic variants impact this causal chain is essential. Although 2 percent of the population over age 65 are clinically diagnosed with Parkinson’s disease, the defining pathology of disease (alpha-synuclein Lewy bodies) is discovered in 20 percent of brains from population-based autopsy studies. We are therefore investigating the impact of genomic variation on directly measured Lewy pathology, neuronal loss in the midbrain substantia nigra, and progressive motor impairment, leveraging human subject cohorts with detailed clinical and pathological data. We also participate in collaborative studies for the functional genetic dissection of Alzheimer’s disease, focusing on the responsible neuropathology, amyloid neuritic plaques and Tau neurofibrillary tangles.
Drosophila Genetics: Despite the promise of current human genetic methods, such as genome-wide association studies, they often fail to identify disease susceptibility genes with certainty, instead highlighting broad genomic regions. We are taking advantage of the rapid and powerful genetics available in the fruit fly Drosophila melanogaster in order to accelerate the validation of responsible genes and an understanding of their functions in disease pathogenesis. Expression of human amyloid-beta, Tau, or alpha-synuclein proteins in the fly nervous system recapitulates many core features of Alzheimer’s disease and Parkinson’s disease pathogenesis. We are testing candidate human susceptibility genes for functional genetic interactions in these fly models of neurodegeneration. Implicated molecular pathways are probed in greater depth, using both Drosophila and human genetic approaches. Our strategy has recently identified cell adhesion converging on the cytoskeleton as likely important for Tau-mediated neurodegeneration and Alzheimer’s disease susceptibility, and we are now following up these insights to elucidate the detailed mechanisms.
- De Jager PL, Shulman JM, Chibnik LB, Keenan BT, Raj T, Wilson RS, Yu L, Leurgans SE, Tran D, Aubin C, Anderson CD, Biffi A, Corneveaux JJ, Huentelman MJ; Alzheimer's Disease Neuroimaging Initiative, Rosand J, Daly MJ, Myers AJ, Reiman EM, Bennett DA and Evans DA. A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiol aging, 33(5): 1017. e1-15 (2012) PubMed
- Buchman AS, Shulman JM, Nag S, Leurgans SE, Arnold SE, Morris MC, Schneider JA and Bennett, D.A. Nigral pathology and parkinsonian signs in elders without Parkinson disease. Ann Neurol, 71(2): 258-66 (2012) PubMed
- Shulman, J.M., Chipendo, P., Chibnik, L.B., Aubin, C., Tran, D., Keenan, B.T., Kramer, P.L., Schneider, J.A., Bennett, D.A., Feany, M.B., and De Jager, P.L. Functional screening of Alzheimer pathology genome-wide association signals in Drosophilia. Am J Hum Genet, 88(2):232-8 (2011) PubMed
- Treusch, S., Hamamachi, S., Goodman, J.L., Matlack, K.E., Chung, C.Y., Baru, V., Shulman, J.M., Parrado, A., Bevis, B.J., Valastyan, J.S., Han, H., Lindhagen-Persson, M., Reiman, E.M., Evans, D.A., Bennett, D.A., Olofsson, A., DeJager, P.L., Tanzi, R.E., Caldwell, K.A., Caldwell, G.A., and Lindquist, S. Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast. Sciencem 334(6060):1241-5 (2011) PubMed
- Shulman JM, De Jager PL and Feany MB. Parkinson's disease: genetics and pathogenesis. Annu Rev Pathol, 6:193-222 (2011) PubMed
- Chibnik LB, Shulman JM, Leurgans SE, Schneider JA, Wilson RS, Tran D, Aubin C, Buchman AS, Heward CB, Myers AJ, Hardy JA, Huentelman MJ, Corneveaux JJ, Reiman EM, Evans DA, Bennett DA and De Jager PL. CR1 is associated with amyloid plaque burden and age-related cognitive decline. Ann Neurol, 69(3):560-9 (2011) PubMed
- Shulman JM, Chibnik LB, Aubin C, Schneider JA, Bennett DA and De Jager PL. Intermediate phenotypes identify divergent pathways to Alzheimer's disease. PLoS One, 5(6):e11244 (2010) PubMed
Joshua M. Shulman, M.D., Ph.D.
Jan and Dan Duncan Neurological Research Institute
1250 Moursund St. Suite N.1150
Houston, TX 77030