BBS Faculty Member - Michael Wolfe

Michael Wolfe

Department of Neurology
Department of Biological Chemistry and Molecular Pharmacology

Brigham and Women's Hospital, Center for Neurologic Diseases
HIM Building, Room 754
4 Blackfan Circle
Boston, MA 02115
Tel: 617-525-5511
Fax: 617-525-5252
Email: mwolfe@rics.bwh.harvard.edu
Lab Members: 7 postdoctoral fellows, 1 graduate student
Visit my lab page here.



The general theme of the lab is understanding the molecular basis of Alzheimer’s disease (AD) and related dementias and exploring new strategies for therapeutic intervention. One focus of the lab has been on gamma-secretase, a membrane-embedded protease that produces the amyloid beta-peptide (A-beta) implicated in the pathogenesis of AD. This protease also plays a variety of critical roles in biology. Small organic inhibitors were developed and used as tools to characterize and identify gamma-secretase. The lab discovered that gamma-secretase is a complex of four different integral membrane proteins, with presenilin as the catalytic component of an unusual aspartyl protease. Purification of the complex has allowed biochemical and structural characterization and a clearer understanding of how inhibitors and modulators interact with the enzyme. Ongoing projects include structural and mechanistic studies on presenilin and presenilin-like proteases and the discovery of gamma-secretase modulators as therapeutic prototypes.

A more recent focus of the lab is RNA splicing in AD and related dementias. Of special interest is the RNA splicing of tau. Filaments of the protein tau are a common feature in a variety of dementias, including AD. Mutations in the tau gene are associated with dementia, and many of these mutations alter a specific RNA splicing event. The Wolfe lab validated the in vivo existence of a hypothetical structure that regulates this splicing and is disrupted by dementia-causing mutations. Screening identified small molecules that interact with and stabilize this structure, and efforts are ongoing to improve these agents to provide new tools for chemical biology and new prototype therapeutics. In addition, a study of the splicing of beta-secretase (also called BACE1), the other protease involved in A-beta production, demonstrated that alternatively splicing leads to inactive isoforms of the enzyme and that shunting splicing down these alternative pathways can lower A-beta levels, suggesting modulation of beta-secretase splicing as a therapeutic strategy.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Wolfe MS. Intramembrane proteolyses. Chemical Reviews 2009, 109, 1599-1612.

Wolfe MS. Tau mutations in neurodegenerative diseases. J. Biol. Chem, 2009, 284, 6021-5.

Quintero-Monzon O, Martin MM, Fernandez MA; Cappello CA, Krzysiak AJ, Osenkowski P, Wolfe MS. Dissociation between processivity and total activity of gamma-secretase: implications for the mechanism of Alzheimer-causing presenilin mutations. Biochemistry 2011; 50(42): 9023-35.

Fisette JF, Montagna DR, Mihaelescu MR, Wolfe MS. A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing. J. Neurochem. 2012; 121(5): 763-73.

Peacey E, Rodriguez L, Liu Y, Wolfe MS. Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing. Nucleic Acids Res., in press.



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