Jie Shen is Associate Professor of Neurology at Harvard Medical School. She received her Ph.D. in molecular biology from the University of Virginia in 1995 studying mechanisms of alternative splicing in Drosophila. As a postdoctoral fellow with Susumu Tonegawa at MIT, she began the investigation of the molecular basis of Alzheimer’s disease using mouse genetic approaches. Since 1998, she has been directing a molecular neurobiology laboratory at Harvard Medical School whose major research interests focus on the pathogenesis of Alzheimer’s and Parkinson’s diseases. Specifically, the Shen laboratory employs a multidisciplinary approach to investigate the molecular and cellular mechanisms that underlie the pathologic degeneration of specific neuronal populations in the adult central nervous system. Through the generation and analysis of mouse models carrying mutations in disease genes, the Shen laboratory has identified a number of early impairments that may trigger the pathogenic cascade leading to neurodegeneration. For example, recent studies from the Shen laboratory demonstrated that inactivation of presenilins, the major gene products responsible for familial AD, in the adult cerebral cortex results in memory and synaptic plasticity impairments followed by progressive neurodegeneration. The deficits caused by inactivation of presenilins are accompanied by specific molecular changes in the central pathways governing long-term memory, synaptic plasticity and neuronal survival. These findings provide evidence for a loss of function pathogenic mechanism in Alzheimer's disease, and suggest that synaptic dysfunction is the early pathogenic event leading to neuronal degeneration. Similarly, the Shen laboratory has started to investigate systematically in mice the function of genes involved in human Parkinson's disease. Studies of parkin-null mice in the Shen laboratory revealed that nigrostriatal and mitochondrial dysfunction precede nigral degeneration, suggesting that these functional defects may underlie the pathogenesis of parkinsonism. More recently, analysis of DJ-1 knockout mice indicated an essential role of DJ-1 in the dopaminergic system and D2 receptor mediated functions. The Shen laboratory is continuing its investigation of the molecular and cellular mechanisms of neurodegenerative diseases using genomic, proteomic, genetic, biochemical, cell biological, electrophysiological and behavioral approaches.