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Michael S. Wolfe, PhD
Senior Scientist, Brigham and Women's Hospital
Visiting Professor of Neurology, Harvard Medical School

Brigham and Women's Hospital
Department of Neurology
75 Francis Street
Boston, MA 02115

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Research Narrative:

 The Wolfe lab studies intramembrane proteases that play critical roles both in normal biology and in human disease. The last place in the cell to expect hydrolysis is within the hydrophobic environment of the lipid bilayer. Nevertheless, a number of multi-pass membrane proteins appear to carry out this seemingly paradoxical process (Wolfe and Kopan, Science, 2004; see publications list for references in this section). Such proteases cut within the transmembrane region of their respective substrates, and consistent with this observation, these proteases contain putative catalytic residues located within transmembrane domains.
The specific focus of the lab has been on the chemistry and biology of
gamma-secretase. This protease is critical to the pathogenesis of Alzheimer's disease (Esler and Wolfe, Science, 2001) and to cell differentiation during embryonic development. Small organic inhibitors were developed and used as tools to characterize and identify gamma-secretase (Wolfe et al., J Med Chem, 1998; Wolfe et al., Biochemistry, 1999a). Findings from the lab implicate a multi-pass membrane protein called presenilin as the catalytic component of a larger gamma-secretase complex (Wolfe et al., Nature, 1999; Esler et al., Nat Cell Biol, 2000). Missense mutations in presenilin cause hereditary Alzheimer's disease, and these mutations specifically affect gamma-secretase activity.

The lab found that presenilin and a presenilin-associated protein called nicastrin copurify with gamma-secretase activity from an immobilized inhibitor, evidence that nicastrin is also a member of the protease complex (Esler et al., Proc Natl Acad Sci USA, 2002). Moreover, a gamma-secretase substrate also copurified, suggesting an initial substrate docking site on the protease complex distinct from the active site. Helical peptides designed to interact with this docking site can potently inhibit g-secretase activity both in cell-free and cell-based assays (Das et al., J Am Chem Soc, 2003; Kornilova et al., Proc Natl Acad Sci USA, 2005).  The lab also determined the stoichiometry of the active g-secretase complex, which had been unknown (and, with respect to presenilin, controversial). The four essential components (presenilin, nicastrin, Aph-1 and Pen-2) are each represented only once per complex (Sato et al., J Biol Chem, 2007).  Disease-causing mutations in presenilin alter processive proteolysis by gamma-secretase, leading to increased proportions of long Ab peptides (Quintero-Monzon et al., Biochemistry, 2011).

The lab also discovered a nucleotide binding site on the gamma-secretase complex.  Small organic molecules that interact with this site can selectively block gamma-secretase proteolysis of the amyloid-b precursor protein (APP), critical to the pathogenesis of Alzheimer’s disease, without affecting proteolysis of an alternative substrate, the Notch receptor.  Notch signaling, critical in many cell differentiation events, requires proteolysis by gamma-secretase (De Strooper et al., Nature, 1999), and blocking Notch signaling with gamma-secretase inhibitors causes severe toxicity in mice.  The finding that compounds can selectively block the cleavage of APP without affecting that of Notch (Fraering et al., J Biol Chem, 2005) has revived this protease as a therapeutic target.  In 2006, Dr. Wolfe cofounded the Laboratory for Experimental Alzheimer Drugs (LEAD) at HMS to advance the development of such selective agents as disease-modifying therapeutics for Alzheimer’s disease.

The Wolfe lab has also investigated the structure, mechanism, and inhibition of other intramembrane proteases, such as the serine protease Rhomboid (Urban and Wolfe, Proc Natl Acad Sci USA, 2005) and the presenilin homolog signal peptide peptidase (Sato et al., Biochemistry, 2006; Narayanan et al., J Biol Chem, 2007; Sato et al., J Biol Chem, 2008), both of which are highly conserved across evolution and play critical roles in biology.  In this way, the lab helped establish common biochemical principles and strategies for designing inhibitors for this family of membrane-embedded enzymes.

The lab has also begun to combine chemistry and biology toward the study of another factor critical to the pathogenesis of dementias: the microtubule-associated protein tau.  Filaments of tau are a common feature in a variety of different neurodegenerative diseases, including Alzheimer’s disease.  Mutations in the gene encoding this protein are associated with dominant, familial forms of frontotemporal dementia, and many of these mutations alter pre-mRNA splicing to increase inclusion of exon 10.  The Wolfe lab has validated the in vivo existence of a hypothetical stem-loop at the end of exon 10, where many of the dementia-associated mutations occur (Donahue et al., J Biol Chem, 2006).  These mutations destabilize this RNA stem-loop structure, allowing more ready access to splicing factors.  High-throughput screening has led to identification of small molecules that interact with and stabilize this structure (Donahue et al., J Biomol Screen, 2007), and NMR studies have elucidated how one of these compounds interacts with the tau mRNA stem-loop (Zhang et al., Chem Biol, 2009).  Efforts are ongoing to improve the potency and selectivity of these agents (Liu et al., J Med Chem, 2009) to provide new tools for chemical biology as well as new prototype therapeutics.  In addition, the lab has studied alternative splicing of the b-site APP-cleaving enzyme 1 (BACE1; b-secretase), determining that alternative splice isoforms are catalytically inactive and that shunting BACE1 down these alternative pathways with antisense oligonucleotides effectively lowers Ab production in cells (Mowrer and Wolfe, J Biol Chem, 2008).  A G-quadruplex structure in exon 3 of BACE1 mRNA partly regulates alternative splicing (Fisette et al., J Neurochem, 2012).  Thus, modulation of BACE1 alternative splicing represents a new strategy for developing therapeutics for Alzheimer’s disease.

Dr. Wolfe is committed to graduate-level teaching at HMS.  In 2003, he co-directed and taught a new quarter course, Neurobiology 300, “Biochemistry and Biology of Neurodegenerative Diseases”, a 2-hour-per-week class with some didactic presentation but primarily discussion of seminal and current research articles in the field.  In 2005 and 2007, he directed and taught this course in its entirety, and in 2009 and 2011, he was joined by Dr. Matthew Lavoie, a junior faculty expert in Parkinson’s disease.  Each time it has been offered, the course has received high praise from students.  From 2002-5, Dr. Wolfe was also involved in leading a discussion section of BCMP 201, “Proteins: Structure, Function, and Catalysis”; in 2006-10, he presented lectures on enzyme mechanisms and inhibition for this course.  In 2004, he also led a discussion section for Med Sci 300, the Conduct of Science, an ethics course required of all DMS graduate students.

University of Kansas, 1990, PhD

Potamkin Prize for Research in Pick’s, Alzheimer’s and Related Diseases, American Academy of Neurology
MetLife Award for Medical Research, MetLife Foundation
Zenith Fellows Award, Alzheimer’s Association
Alzheimer Drug Discovery Foundation and Elan Pharmaceuticals, Award for Innovative Research
Annual Alumni Award, University of the Sciences in Philadelphia
Sato Memorial International Award, Pharmaceutical Society of Japan