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    Hilal A. Lashuel, Ph.D.
      Instructor of Neurology

 

    Center for Neurologic Diseases

    Brigham & Women’s Hospital and

    Harvard Medical School

    65 Landsdowne St

    Cambridge, MA 02149

    Tel  617-768-8621

    Fax 617-768-8606

    hlashuel@hms.harvard.edu

 

 

 

Education:

 

1994               B.S.     City University of New York, Brooklyn College  (Chemistry)   

1999               Ph.D.   Texas A&M University (Organic Chemistry)

Predoctoral Training:

1994-1999:

Graduate student in the laboratory of Dr. Jeffery W. Kelly at Texas A&M University, College Station, TX, and ThScripps  Research Institute, La Jolla, CA: Ph.D. thesis concerned

“Biophysical studies on the acid denaturation of Transthyretin: understanding the mechanism of amyloid fibril formation in human amyloid diseases”.

“Design, synthesis, and biophysical characterization of peptidomimetic-based model systems for understanding amyloid fibril formation in neurodegenerative diseases”

 

Postdoctoral Training:

 

2000-2001      Research fellow at the Picower Institute for Medical Research, Manhasset, New York.

 

2001-2002      Research fellow in laboratory of Dr. Peter T. Lansbury at Brigham and Women’s Hospital and Department of Neurology,

                       Harvard Medical School, Boston, MA

 

2001-2002      Sabbatical fellow in the Laboratory for Drug Discovery in Neurodegeneration, Core D of the Harvard Center for

                       Neurodegeneration and Repair (HCNR), Harvard Medical School, Boston, MA.

 

Academic Appointments:

 

1994-1997       Teaching Graduate Assistant, Texas A&M University, College Station, TX.

 

2002- present   Instructor of Neurology, Harvard Medical School and Brigham & Women’s Hospital, Boston, MA.

 

Current Research Interest:

Our current research efforts are directed at understanding the biochemical mechanism of amyloid fibril formation by the amyloidogenic proteins a-synuclein and amyloid-b (Ab) and how it contributes to the pathogenesis of Parkinson’s and Alzheimer’s disease respectively. My current research interests are focused in three areas: 1) elucidating the structural properties of the early intermediates on the pathway of Ab and a-synuclein fibril formation, the relationship between the different intermediates and their structural relationship to the structure of the final product, the amyloid fibrils; 2) investigating the interactions between the amyloidogenic proteins Ab and a-synuclein with membranes and lipid bilayers with the emphasis on elucidating the structural properties (secondary, tertiary and quaternary structural changes) of the functional and membrane active Ab and a-synuclein intermediate(s); 3) to identify drug-like molecules “molecular probes” that can be used to perturb (enhance or suppress) Ab and a-synuclein amyloid fibril formation in vitro and in vivo. These molecules will be used as research tools to elucidate the role of the process of amyloid fibril formation in the pathogenesis of AD and PD in cell culture systems as well as transgenic animals.

 

Publications: *corresponding author equal contribution.

1.                Lashuel HA & Lansbury PT.  " How do Protein Aggregates Kill Neurons?". Molecular Cell. 2004, Submitted.

2.                Lashuel HA, Hartley D, Petre B, Wall, Simon M, Walz T, Lansbury PT . Mixtures of wild-type and a pathogenic (E22G) form of Ab40 in vitro accumulate protofibrils, including amyloid pores. J. Mol. Biol. 2003, 332, 795-805.

3.                Ferrao-Gonzales AD, Palmieri L, Valory M, Silva JL, Lashuel HA, Kelly JW, Foguel D. Hydration and Packing are Crucial to Amyloidogenesis as Revealed by Pressure Studies on Transthyretin Variants that Either Protect or Worsen Amyloid Disease. J. Mol. Biol.  2003, 328, 4, 963-974.

4.                Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J, Yeh L, Cuny, GD, Stein RL, and Lansbury PT, Jr.  A Class of Small Molecule UCH-L1 Inhibitors: Chemical Genetic Tools to Probe the Pathogenesis of Parkinson’s Disease and Cancer. 2003, Chemistry & Biology.  2003, 10, 837-846.

5.                Kheterpal I, Lashuel HA, Hartley DM, Walz T, Lansbury PT Jr., Wetzel R. Aβ protofibrils possess a stable core structure resistant to hydrogen exchange. Biochemistry. 2003, 42, 14092-14098.

6.                Foguel D, Suarez MC, Ferrão-Gonzales AD, Porto TR, Palmieri L, Einsiedler C, Lashuel HA, Lansbury PT, Kelly JW, and Silva JL. Dissociation of Amyloid Fibrils of a-Synuclein and Transthyretin by Pressure Reveals their Reversible Nature and the Formation of Water-Excluded Cavities. Proceeding of the National Academy of Science. 2003, 100, 9831-9836.

7.                Bitan G, Tarus B, Lashuel HA, Vollers SS, Condron MM, Straub E, Teplow DB. A Molecular Switch in Amyloid Assembly: Met35 and Amyloid b-protein Oligomerization. Journal of the American Chemical Society. 2003, 125, 15359-15369.

8.                Lashuel HA, Aljabari B, Metz C, Bucala R, Callaway DE. Amyloid Fibril Formation by Macrophage Migration Inhibitory Factor (MIF). FEBS Letters, submitted.

9.                Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Hayashi Y, Walz T, and Sheng M. EM Structure, Protein Dynamics and Synaptic Function of SAP97, and AMPA Receptor Scaffold Protein. Neuron, Submitted.

10.              Lashuel HA, Hartley D, Petre B, Walz T, Lansbury PT. Neurodegenerative Diseases, Amyloid Pores from Pathogenic Mutations. Nature. 2002, 418, 291.

a.        C&EN: Science & Technology - What‘s Behind Amyloid Diseases? , By Sophie L. Wilkinson Chemical & Engineering News, 80 (32), August 12, 2002 

11.             Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury PT. The UCH-L1 Gene Encodes Two Opposing Enzymatic Activities that Affect alpha-Synuclein Degradation and Parkinson's Disease Susceptibility. Cell. 2002 ,111, 209-218.

a.        Science: Deadly Giveaway, Protein linked to Parkinson's disease squanders clearance molecules, By John R. Davenport . Science Magazine October 23, 2002. http://sageke.sciencemag.org/cgi/content/abstract/sageke;2002/42/nw145.

b.       Focus: Enzyme Linked to Pathology of Parkinson’s Disease Appears Two-faced: Protein's Reckless Side May Lead to Deadly Pileups in the Cell. By Courtney Humphries, November 8, 2002. http://focus.hms.harvard.edu

12.             Lashuel HA*, Hartley D, Balakhaneh D, Teichberg S, Callaway DE*. New Class of Inhibitors of  Amyloid-b (Ab) Fibril Formation: Implications for the Mechanism of Pathogenesis in Alzheimer’s disease. J. Biol. Chem. 2002, 277: 42881-42890.

13.             Lashuel HA, Petre B, Wall, Simon M, Nowak RJ, Walz T, Lansbury PT. a-Synuclein, Especially the Parkinson’s Disease-Associated Mutants, Form Pore-like Annular and Tubular Protofibrils.  J. Mol. Biol. 2002 , 322, 5, 1089-1102.

14.             Wang, L, Lashuel HA, Walz, T. and Colon F. Serum Amyloid A Forms a Hexamer with a Central Channel. Proceeding of the National Academy of Science, 2002,  99, 15947-15952.

15.             Oza VB, Smith C, Raman P, Koepf EK,, Lashuel HA, Petrassi M, Chiang K, Powers ET, Sachettinni J, and Jeffery W. Kelly. J. Synthesis, structure, and activity of diclofenac analogues as transthyretin amyloid fibril formation inhibitors. Med. Chem., 2002, 45, 321-332.

16.             Lashuel HA, LaBrenz SR, Woo L, Kelly JW. A Peptidomimetic that forms Cables, Monolayers (or Bilayers) or Fibrils Depending on Solution Conditions: Implications For Material Science and Neurodegenerative Diseases. Journal of the American Chemical Society, 2000, 122, 22, 5262-5277.

17.             Gingolani G, Lashuel HA, Gerace L, Müller CW. Nuclear import factors importin a and b importin undergo mutually induced conformational changes upon association. FEBS Letters, 2000, 484, 291-298.

18.             Liu K, Cho HW, Lashuel , Kelly JW, Wemmer DE. A Glimpse of a Possible Amyloidogenic Intermediate of Transthyretin. Nature Structural Biology, 2000, 7, 754-757. 

19.             Lashuel HA, Wurth C, Woo L, Kelly JW. The Most Pathogenic Transthyretin FAP-Associated Variant, L55P, Forms Amyloid Fibrils Under Physiological and Acidic Conditions. Biochemistry, 1999, 38, 13560 - 13573.

20.             Atkins AR, Lashuel HA, Kelly JW, Edelman GW, Wright PE, Cunningham BA, Dyson J. Association between the first two Immunoglobulin-like domains of the Neural Cell Adhesion Molecule N-CAM.  FEBS Letters, 1999, 451, 162-168.

21.             Chitnumsub P, Fiori WR, Lashuel HA, Diaz H. Kelly JW. The Nucleation of Monomeric Parallel b-Sheet-like Structures in Aqueous Solutions. Bioorganic & Medicinal Chemistry. 1999, 7, 1, 39-59.

22.             Lashuel HA, Lai Z, Kelly JW. Characterization of the Transthyretin Acid Denaturation Pathway by Analytical Ultracentrifugation: Implications for wild type, V30M and L55P Amyloid Fibril Formation. Biochemistry. 1998, 37, 51, 17851-17864.

23.             Patricelli MP, Lashuel HA, Kelly JW, Cravatt BF. Comparative Characterization of Wild Type and Transmembrane Domain-Deleted Fatty Acid Amide Hydrolase: Identification of the Transmembrane Domain as a Site for Oligomerization. Biochemistry 1998 37, 15177-1518.

24.             Xie Y, Lashuel HA, Miroy GJ, and Kelly JW. Efficient Refolding and Characterization of Recombinant Human Plasma Retinal-Binding Protein from Inclusion Bodies in E.coli. Protein Expression and Purification. 1998, 14, (1), 31-37.

25.             Hengst L, Lashuel HA, Reed SI. One Molecule of p21Kip1Is Sufficient to Inhibit One CdK/Cyclin Complex. Genes & Development. 1998, 12, 3882-3888.

26.             Peterson SA, Klabunde T, Lashuel HA, Purkey H, Sacchettini JC, Kelly JW. Inhibiting Transthyretin Conformational Changes that Lead to Amyloid Fibril Formation. Proceedings of the National Academy of Science. U.S.A.  1998, 95, 12956-12960.

27.             Xiangang Z, Zhu H, Lashuel HA, Hu J. Probing the Oligomerization Properties of GCN4 Leucine Zipper e & g Position Mutants.  Protein Science. 1997, 6, 2218-2226.

28.             Colon W, Zhihong L, Lashuel HA, McCulloch J, McCutchen S, Miroy GJ, Peterson SA, Kelly JW.  Transthyretin Conformational Changes Facilitate Misassembly into Amyloid: A New Therapeutic Strategy Based on Preventing the Amyloidogenic Conformational Changes. Advances in Protein Chemistry, “Protein Misassembly” 1997, 161-179.  Edited by Ronald Wetzel, Academic Press.

29.             Lai Z, McCulloch J, Lashuel HA, Kelly JW. GdnHCL Induced Denaturation and Refolding of Transthyretin Exhibits a Marked Hysteresis: Equilibria with High Kinetic Barriers. Biochemistry. 1997, 36, 33, 10230-10239.

30.             Miroy GJ, Zhihong L, Lashuel HA, Peterson SA, Strang C, Kelly JW. Inhibiting Amyloid Fibril Formation via Protein Stabilization. Proceedings of the National Academy of Science. U.S.A. 1996, 93, 15051-1505.

Patents:

1.                 Miroy GJ, Kelly JW, Lai Z, Lashuel HA, Petterson SA. Anit-Amyloidogenic Agents.PCT Int. App., 68pp. CODEN: PIXXD2. WO 9827972 A2, 980702. CAN 129:100056 CAPLUS.

2.                 Lashuel HA, Callaway DE. Aporphine Inhibitors of Amyloid-b (Ab) Fibril Formation and their Use in Amylodosis-Based Disease. (Docket NO: 9511-083-27 PROV).

Meeting Reports:

1.           Kimberly TW, Kovacs DM, Walsh D, Lashuel HA, Lemere CA. The 8th International Conference on Alzheimer’s Disease and Related Disorders. Amyloid, 2003, 10, 51-61.

Invited Review Articles, Book Chapters:

 

1.               Lashuel HA*. In Vitro Preparation of Prefibrillar Intermediates of Amyloid-b (Ab) and a-Synuclein. In Amyloidogenic Proteins – Methods in Molecular Biology, Edited by Einar M. Sigurdsson. Humana Press, USA (2004), In press.
 

2.               Lashuel HA* and Joseph Wall. Molecular Electron Microscopy Approaches to Elucidating the Mechanism of Amyloid Fibril Formation. Methods in Molecular Biology, Edited by Einar M. Sigurdsson. Humana Press, USA (2004), In press.

National and international invited lectures (selected):

2001

1.           King Fahed University of Petroleum and Minerals, Department of Chemistry Seminar, Dhahran, Saudi Arabia, April, 2001.
 

2002
 

2.           University of California San Francisco, “Physical Properties of Amyloid Diseases”, San Francisco, CA. December, 25-27 2002.

3.           Parkinson’s Institute, “Protein Fibrillogenesis in Parkinson’s Disease”, Sunnyvale, CA.

December, 28 2002.

4.           Massachusetts Institute of Technology, Department of Biology: “Structural Biology Seminar”,

March, 18, 2002.

5.           American Chemical Society National Meeting, “Structural and Mechanistic Aspects of Amyloid Fibril Formation” Orlando Florida, April, 7-11 2002.

6.           FASEB Meeting,: “Amyloid and Other Abnormal Protein Processes”, Colorado, June, 15-20 2002.

7.           Biogen,Inc, Cambridge, MA, September, 6th, 2002.

8.           Protein Folding and Disease: The Horizon Symposia “ Protein Folding and Disease” organized by Nature Publishing Group and Aventis. Verona, Italy, October, 2-5th 2002.

9.           Elan BioPharmaceuticals, San Francisco, CA, October 13, 2002.

10.             RIKEN Brain Science Institute: The first international workshop of molecular neuropathology “Frontiers in Molecular Neuropathology” Japan,  November, 27-29 2002.

2003

11.        Boehringer Ingelheim Fonds Internalional Titisee Conferences “ Alzheimer’s and Parkinson’s Disease: From Basic Science to Therapeutic Treatment. Germany, Titise/Black Forest, March 19-23, 2003.

12.           Third Multidisciplinary Workshop,: “Self-assembling Peptides & Protein Systems in Biology, Medicine  and Engineering” Crete, Greece,  August,  2003.

13.           Lady Davis Institute for Medical Research, Montreal, Canada, August 27th, 2003.

14.             Rensselaer Polytechnic Institute, Department of Chemistry Seminar Series. “Protein fibrillogenesis in Neurodegenerative Diseases: From Biophysics to Therapeutic Strategies.  Albany, NY September 2nd, 2003.

15.              University of Rhode Island's Department of Biomedical Sciences, Rhode Island, November 2003.

 

2004
 

16.              10th Neural Workshop Verbier, “Molecular, Cellular and Clinical Aspects of Neurodegenerative   Diseases” Verbier, Switzerland, January, 2004.

17.              Institute for Complex Adaptive Matter Workshop. Protein Misaggregation: from Biomolecules to Neurodegeneration. Boston, MA, February 9th- 11, 2004.

18.              Washington University in St. Louis, School of Medicine. Department of Neurology, April 20th, 2004.

19.              Clark Universitty, Department of Chemistry and Biochemistry. Worcester, MA, April 28th, 2004.

20.              Dutch Endo Neuro Psycho meeting of 2004Amsterdam, Netherlands June 1-3, 2004. Annual meeting for scientists of fundamental and clinical endocrinology, neuroendocrinology and neuroscience. 

21.             Netherlands Brain Institute, Amsterdam, Netherlands,  June 4th, 2004.

22.             Summer Neuropeptide 2004 Conference, Miami, July 5-9, 2004.