Description of Research Expertise:
My research interests are focused in the genetics of neurodegenerative diseases, in particular frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). My lab partners with Penn neurologists working in these areas and the Center for Neurodegenerative Diseases for neuropathology and biochemistry to collect DNA from living individuals and brains from autopsy cases to conduct genetic and genome-wide studies to better understand these diseases and identify therapeutic targets. We also work with 2 genetic counselors and have a special interest in the education of patients and the translation of the genetic findings from research labs to CLIA-certified clinical labs so it can benefit patients and families in our research cohort as well as the population at large.
FTLD manifests clinically with progressive behavioral and/or language deficits. Subtypes of FTLD are classified neuropathologically by the protein composition of cellular inclusion bodies. The most common neuropathological correlates of FTLD have TAR DNA binding protein (TDP-43) inclusions (FTLD-TDP) or tau inclusions (FTLD-tau). FTLD is frequently familial and can occur as an autosomal dominantly inherited disorder. Genes with mutations causing FTLD include MAPT (encodes tau) and GRN (encodes progranulin) among others, each of which is associated with a specific FTLD pathological subtype: GRN mutations with FTLD-TDP and MAPT mutations with FTLD-tau. Studying the genetics of FTLD can help elucidate its etiology and pathophysiology and provide targets for therapy as well as identify risk factors that modify disease risk or phenotype. We perform genetic analysis of FTLD, ALS, PD, and AD to identify mutations in known genes as well as novel genes and study them in families to determine pathogenicity, phenotypic variability and correlations with brain pathology. Several recent major projects led to teh identicication of TARDBP (TDP-43) mutations in ALS and a genome-wide association study of FTLD-TDP which identified a novel genetic risk factor, TMEM106B. Many new avenues of research in these areas are being pursued.
Diamond Joshua M, Cantu Edward, Porteous Mary, Suzuki Yoshikazu, Meyer Keith C, Lederer David, Milewski Rita K, Arcasoy Selim, D'Ovidio Frank, Bacchetta Matthew, Sonett Joshua R, Singh Gopal, Costa Joseph, Tobias John W, Rodriguez Hetty, Van Deerlin Vivianna M, Olthoff Kim M, Shaked Abraham, Chang Bao-Li: Peripheral Blood Gene Expression Changes Associated with Primary Graft Dysfunction after Lung Transplantation. Am J Transplant 17 (7): 1770-1777,2017.
Cairns NJ, Irwin DJ, Van Deerlin VM, Lee VM-Y: Genetics and Neuropathology of Frontotemporal Dementia. The Human Frontal Lobes: Functions and Disorders : 2017 [in press].
Lee EB, Porta S, Michael BG, Xu Y, Suh ER, Kwong LK, Elman L, Grossman M, Lee V M-Y, Irwin DJ, Van Deerlin VM: Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration. Acta Neuropathol 134 (1): 65-78,2017.
Jun Gyungah R, Chung Jaeyoon, Mez Jesse, Barber Robert, Beecham Gary W, Bennett David A, Buxbaum Joseph D, Byrd Goldie S, Carrasquillo Minerva M, Crane Paul K, Cruchaga Carlos, De Jager Philip, Ertekin-Taner Nilufer, Evans Denis, Fallin M Danielle, Foroud Tatiana M, Friedland Robert P, Goate Alison M, Graff-Radford Neill R, Hendrie Hugh, Hall Kathleen S, Hamilton-Nelson Kara L, Inzelberg Rivka, Kamboh M Ilyas, Kauwe John S K, Kukull Walter A, Kunkle Brian W, Kuwano Ryozo, Larson Eric B, Logue Mark W: Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimer's & dementia : the journal of the Alzheimer's Association : 2017.
Cooper Christine A, Jain Nimansha, Gallagher Michael D, Weintraub Daniel, Xie Sharon X, Berlyand Yosef, Espay Alberto J, Quinn Joseph, Edwards Karen L, Montine Thomas, Van Deerlin Vivianna M, Trojanowski John, Zabetian Cyrus P: Common variant rs356182 near SNCA defines a Parkinson's disease endophenotype. Ann Clin Transl Neurology 4 (1): 15-25,2017.
Suh E*, Lee EB*, Neal D, Wood EM, Toledo JB, Rennert L, Irwin DJ, McMillan CT, Krock B, Elman LB, McCluskey LF, Grossman M, Xie SX, Trojanowski JQ: Semi-automated quantification of C9orf72 expansion size reveals inverse correlation between hexanucleotide repeat number and disease duration in frontotemporal degeneration Acta Neuropathol 130 (3): 363-72,2015.
Yu CE, Bird TD, Bekris LM, Montine TJ, Leverenz JB, Steinbart E, Galloway NM, Feldman H, Woltjer R, Miller CA, Wood EM, Grossman M, McCluskey L, Clark CM, Neumann M, Danek A, Galasko DR, Arnold SE, Chen-Plotkin A, Karydas A, Miller BL, Trojanowski JQ, Lee VM, Schellenberg GD: The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration Arch Neurol 67(2): 161-70 : 2010.
Van Deerlin VM, Sleiman PMA, Martinez-Lage M, Chen-Plotkin A, Wang, L-S, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DMA, Pickering-Brown SM, Seelaar H, Heutink P, vanSwieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, Hodges J, Spillantini MG, Gilman S, Lieberman AP, Kaye JA, Woltjer Randall L, Bigio EH, Mesulam M, Al-Sarraj S, Troakes C, Rosenberg RN, White III CL, Ferrer I, Lladó A,
Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller, BL, Alzualde A: Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42 (3): 234–39,2010.
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