Junying Yuan, Ph.D.

Professor of Cell Biology

Department of Cell Biology
Harvard Medical School
SGM, Room 400
250 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-4170
Fax: (617) 432-4177
Email: jyuan@hms.harvard.edu
9 postdoctoral fellows, 5 graduate students

We are interested in understanding the mechanisms of neurodegeneration. The experiments in our laboratory address the basic mechanisms of cell death as well as their implications in neurodegenerative diseases using cellular, genetic, molecular and chemical biological approaches.

Unfolded protein response (UPR) is a cellular stress response to the accumulation of excess unfolded proteins in the endoplasmic reticulum. UPR has been shown to play an important role in mediating neurodegeneration. We found that caspase-12 is specifically expressed in endoplasmic reticulum and a deficiency in caspase-12 renders cortical neurons specifically resistant to amyloid b protein toxicity. Thus, caspase-12 mediates a novel ER-specific apoptosis pathway. We developed a high throughput assay for ER stress and identified a small molecule inhibitor of ER stress induced cell death which we named salubrinal (sal). We showed that sal inhibits ER stress by acting as an inhibitor of GADD34/PP1, a phosphastase complex mediating dephosphorylation of eIF2a.

Apoptosis may not be the only cellular mechanism of cell death. We recently identified a small molecule inhibitor of cellular non-apoptotic cell death named necrostatin-1 (Nec-1). Nec-1 inhibits an alternative cell death pathway, which we named necroptosis, that may function as a backup mechanism when apoptosis fails Necroptosis is characterized morphologically by necrotic phenotype and may be particularly relevant to neurodegeneration. We showed that Nec-1 reduces ischemic brain injury with an extended time window for treatment. Thus, necroptosis may be very important for mediating acute neurological injury.

References:

• Sánchez I, Mahlke C, Yuan J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature. 2003. 421, 373-9.
• Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D and Yuan J. A Selective inhibitor of eIF2a dephosphorylation protects cells from ER stress. Science. 2005. 307, 935-939.
• Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA and Yuan J. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nature Chemical Biology. 2005. 1, 112-119.