Assistant Professor, Baylor College of Medicine
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
Functional genomics of Alzheimer’s disease and Parkinson’s disease; integrative genetic analyses in humans and Drosophila
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 cognition and motor control in humans.
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.
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.
Shulman JM, Benton R, St Johnston D (2000) The Drosophila homolog of C. elegans PAR-1 organizes the oocyte cytoskeleton and directs oskar mRNA localization to the posterior pole. Cell 101:377-388.
Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB (2001) Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711-714.
Shulman JM, Feany MB (2003) Genetic modifiers of tauopathy in Drosophila. Genetics 165:1233-1242.
Shulman JM, Chibnik LB, Aubin C, Schneider JA, Bennett DA, De Jager PL (2010) Intermediate phenotypes identify divergent pathways to Alzheimer’s disease. PLoS One 5:e11244.
Shulman JM, Chipendo P, Chibnik LB, Aubin C, Tran D, Keenan BT, Kramer PL, Schneider JA, Bennett DA, Feany MB, De Jager PL (2011) Functional screening of Alzheimer pathology genome-wide association signals in Drosophila. American Journal of Human Genetics 88:232-238.
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, De Jager PL (2011) CR1 is associated with amyloid plaque burden and age-related cognitive decline. Annals of Neurology 69:560-569.
Treusch S, Hamamichi S, Goodman JL, Matlack KE, Chung CY, Baru V, Shulman JM, Parrado A, Bevis BJ, Valastyan JS, Han H, Lindhagen-Persson M, Reiman EM, Evans DA, Bennett DA, Olofsson A, DeJager PL, Tanzi RE, Caldwell KA, Caldwell GA, Lindquist S (2011) Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast. Science 334:1241-1245.
Shulman JM, De Jager PL, Feany MB (2011) Parkinson’s disease: genetics and pathogenesis. Annual Review of Pathology 6:193-222.
Buchman AS, Shulman JM, Nag S, Leurgans SE, Arnold SE, Morris MC, Schneider JA, Bennett DA (2012) Nigral pathology and parkinsonian signs in elders without Parkinson disease. Annals of Neurology 71:258-266.
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, Evans DA (2012) A genome-wide scan for common variants affecting the rate of age-related cognitive decline. Neurobiology of Aging 33:1017.e1-1017.e15.
Joshua M. Shulman, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
1250 Moursund St. – NRI, Suite N.1150
Houston, Texas 77030, U.S.A.
Tel: (832) 824-8976
Fax: (832) 825-1249