Michael Wolfe, Ph.D.

Professor of Neurology

Brigham & Women's Hospital
Ctr for Neurologic Diseases
HIM Building, Room 754
4 Blackfan Circle
Boston, MA  02115
Telephone: 617-525-5511
Fax: 617-525-5252
Email: mwolfe@rics.bwh.harvard.edu
Lab website: The Wolfe Lab

The Wolfe lab studies membrane-embedded proteases critical in normal biology and in human disease.  The specific focus has been on the chemistry and biology of gamma-secretase, a protease critical to the pathogenesis of Alzheimer's disease and to cell differentiation during embryonic development. Small organic inhibitors have been developed and used as tools to characterize and identify gamma-secretase. Findings from the lab demonstrated that presenilin is the catalytic component of a larger gamma-secretase complex. Missense mutations in presenilin cause hereditary Alzheimer's disease, and these mutations specifically affect gamma-secretase activity.  Purification of the complex has allowed biochemical characterization and a clearer understanding of how inhibitors and modulators interact with the enzyme.  Ongoing projects also include structural studies on presenilin and presenilin-like proteases.

 

The lab has also begun studies on RNA splicing events critical to the pathogenesis of dementias.  One focus is tau, a protein that forms filaments in a variety of neurodegenerative diseases.  Mutations in tau that alter RNA splicing cause frontotemporal dementia.  The lab validated the existence of a hypothetical stem loop where many of the dementia-associated mutations occur.  These mutations destabilize the stem loop, allowing easier access to splicing factors.  Small molecules that interact with and stabilize this structure have been identified, and efforts are ongoing to improve these agents to provide new tools for chemical biology as well as new prototype therapeutics.  A related project is focused on RNA splicing of beta-secretase, which along with gamma-secretase produces the neurotoxic amyloid-beta peptide of Alzheimer’s disease.

References:

• Kornilova AY, Bihel F, Das C and Wolfe MS.  The initial substrate binding site of? g-secretase is located on presenilin near the active site. Proc. Natl. Acad. Sci. USA, 2005,102:9,3230-5.
• Donahue CP, Muratore C, Wu J, Kosik KS, Wolfe MS.  Stabilization of the tau exon 10 stem loop alters pre-mRNA splicing.  J. Biol. Chem. 2006, 281(33): 23302-06.
• Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y, De Strooper B, Steiner H, Haass C, Wolfe MS.  Active g-secretase complexes contain only one of each component.  J. Biol. Chem. 2007, 282(47): 33985-33993.
• Selkoe DJ and Wolfe MS.  Presenilin: running with scissors in the membrane.  Cell 2007, 131: 215-221.
• Mowrer K, Wolfe MS.  Promotion of BACE1 mRNA alternative splicing reduces amyloid b-peptide production.  J. Biol. Chem. 2008, 283: 18694-18701.

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Previous faculty member (Rachel Wilson)