Jie Shen, Ph.D.

Associate Professor of Neurology

Brigham and Women's Hospital
New Research Building 636
77 Avenue Louis Pasteur
Boston, MA 02115
Telephone: 617-525-5561
Fax: 617- 525-5522
Email: jshen@rics.bwh.harvard.edu
Lab website: The Shen Lab

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.

References:

• Saura CA, Choi S, Beglopoulos V, Zhang D, Malkani S, Rao BSS, Chattarji S, Kelleher RJ, Kandel ER, Duff K, Kirkwood A and Shen J. Loss of presenilin function in the adult brain causes memory and synaptic plasticity impairments and age-dependent neurodegeneration. Neuron 2004, 42:23-36.
• Wines ME, Handler M and Shen J. Role of presenilin-1 in cortical lamination and survival of Cajal-Retzius neurons. Dev Biol 2005, 277:332-346.
• Goldberg MS, Pisani A, Haburcak M, Vertherms, TA, Kitada T, Costa C, Tong Y, Martella G, Tscherter A, Martins A, Bernardi G, Roth BL, Pothos EN, Calabresi P and Shen J. Nigrostriatal dopaminergic deficits and hypokinesia caused by inactivation of the familial parkinsonism-linked gene DJ-1. Neuron 2005, 45: 489-96.
• Shen J and Kelleher RJ.  The presenilin hypothesis of Alzheimer’s disease: Evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007, 104: 403-9.
• Kitada T, Pisani A, Porter DR, Yamaguchi H, Tscherter A, Martella G, Bonsi P, Zhang C, Pothos EN, and Shen J. Impaired dopamine release and synaptic plasticity in the striatum of PINK1-deficient mice. Proc Natl Acad Sci U S A. 2007, 104:11441-6.

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