Michael S. 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
Web Page: The Wolfe Lab Page
7 postdoctoral fellows, 1 graduate student
The general theme of the lab is understanding the molecular basis of Alzheimer’s and related dementias and exploring new strategies for therapeutic intervention. One focus of the lab has been on γ-secretase, a membrane-embedded protease that produces the amyloid β-peptide (Aβ) implicated in the pathogenesis of Alzheimer's disease (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 γ-secretase. The lab discovered that γ-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 γ-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 β-secretase, the other protease involved in Aβ production, demonstrated that alternatively splicing leads to inactive isoforms of the enzyme and that shunting splicing down these alternative pathways can lower Aβ levels, suggesting modulation of β-secretase splicing as a therapeutic strategy.
References:
- Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y, De Strooper B, Steiner H, Haass C, Wolfe MS. Active γ-secretase complexes contain only one of each component. J. Biol. Chem. 2007, 282, 33985-33993.
- Mowrer K, Wolfe MS. Promotion of BACE1 mRNA alternative splicing reduces amyloid β-peptide production. J. Biol. Chem., 2008, 283, 18694-18701.
- Wolfe MS. Intramembrane proteolyses. Chemical Reviews 2009, 109, 1599-1612.
- Wolfe MS. Tau mutations in neurodegenerative diseases. J. Biol. Chem, 2009, 284, 6021-5.
BBS webpage updated 12/02/2009