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.