Shen, Jie

Biography

The major research interests of my laboratory focus on elucidation of the pathogenic mechanisms of Alzheimer's and Parkinson's diseases. We employ a multidisciplinary approach based on the generation and analysis of mouse models, with the goal of understanding how pathogenic mutations perturb the normal in vivo function of gene products linked to these disorders. We discovered that the major Alzheimer's disease genes, presenilins, are essential for normal neuronal physiology and survival in the adult brain. Specifically, we found that presenilin inactivation causes striking age-dependent neurodegeneration that strongly resembles the neuropathology of Alzheimer's disease. Neuropathological changes in these mice are preceded by a decrease in presynaptic glutamate release and impairment in NMDA receptor function and synaptic plasticity, suggesting that synaptic dysfunction may trigger subsequent neurodegeneration. Based on these and other findings, we proposed the novel hypothesis that presenilin mutations cause Alzheimer's disease through a loss-of-function pathogenic mechanism. We have also generated mouse models for all genes thus far linked to autosomal recessive Parkinson's disease: parkin, DJ-1 and PINK1. Analysis of these mutant mice revealed important roles for the parkin, DJ-1 and PINK1 gene products in nigrostriatal dopaminergic physiology, suggesting that impaired dopamine release is a common pathophysiological alteration in the disease, and again pointing to impaired synaptic transmission as the initial trigger for neurodegeneration. Thus, our findings support the central hypothesis that synaptic dysfunction, and particularly impaired presynaptic neurotransmitter release, in affected neural circuits plays a crucial role in the pathogenic process leading to synaptic and neuronal loss.

Research Interest

Alzheimer's and Parkinson's diseases.