Peter T. Lansbury, Jr.

Department of Neurology
Brigham and Women's Hospital
Center for Neurologic Diseases
Partners' HealthCare System Building
65 Landsdowne Street, Room 451
Cambridge, MA 02139
Tel: (617) 768-8610
Fax: (617) 768-8606
Email: plansbury@rics.bwh.harvard.edu
Web Page: The Lansbury Lab Page
3 postdoctoral fellows, 5 graduate students

We are interested in the protein pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Our window to these related neurodegenerative diseases is protein structural biology. AD and PD are both characterized by the deposition of fibrillar aggregates (amyloid in AD, the Lewy body in PD) comprising normal neuronal proteins. There is strong circumstantial evidence in each case that aggregation initiates a cascade of events that culminates in neurodegeneration. Since the inhibition of aggregation is a plausible therapeutic strategy it is critical to elucidate the molecular details of aggregate structure as well as the mechanism by which aggregates are formed. Our approach is a reductionist one: purified proteins from recombinant or synthetic sources are studied in vitro under controlled conditions selected to analyze particular factors that may be important in vivo. The structure of the disease-specific fibrillar protein aggregates is analyzed by several developing methods; solid-state NMR, Fourier-transform infrared spectroscopy, and atomic force microscopy. This work involves collaborations between our group and groups that are expert in the relevant technology.

In both AD and PD, the aggregating protein is a normal neuronal protein (Aß in AD, the a-synuclein in PD) of undetermined function. The possibility exists that disease results from a loss of the normal protein, rather than by the accumulation of aggregates. Studies are in progress to determine the normal role of these proteins. These studies involve molecular biological, biochemical and cell biological approaches to the elucidation of protein-protein interactions. Many of our hypotheses will be tested in drosophila and mouse models using small molecules identified by screening

References:

Das C, Hoang QQ, Kreinbring CA, Luchansky SJ, Meray RK, Ray SS, Lansbury PT, Ringe D, Petsko GA. Free in PMC Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1. Proc Natl Acad Sci U S A. 2006 Mar 21;103(12):4675-80. Epub 2006 Mar 13. Erratum in: Proc Natl Acad Sci U S A. 2006 Apr 25;103(17):6776.
Lansbury PT Jr. Improving synaptic function in a mouse model of AD. Cell. 2006 Aug 25;126(4):655-7.
Luchansky SJ, Lansbury PT Jr, Stein RL. Substrate recognition and catalysis by UCH-L1. Biochemistry. 2006 Dec 12;45(49):14717-25.
Volles MJ, Lansbury PT Jr. Relationships between the Sequence of alpha-Synuclein and its Membrane Affinity, Fibrillization Propensity, and Yeast Toxicity. J Mol Biol. 2007 Mar 9;366(5):1510-22. Epub 2006 Dec 21.
Fredenburg, RA, Rospigliosi, C, Meray, RK, Kessler, JC, Lashuel, HA, Eliezer, D, Lansbury, PT Jr. The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states. Biochemistry. 2007; 46 (24), 7107-18. Epub 2007 May 26.
Meray, RK, Lansbury, PT Jr. Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1. J Biol Chem. 2007; 282(14), 10567-75. Epub 2007 Jan 26.
Lieberman, RL, Wustman, BA, Huertas, P, Powe, AC Jr, Pine, CW, Khanna, R, Schlossmacher, MG, Ringe, D, Petsko, GA. Structure of acid beta-glucosidase with pharmacological chaperone provides insight into Gaucher disease. Nature Chem Biol. 2007; 3(2), 101-7.

REVIEWS:

Lashuel HA, Lansbury PT Jr. Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins? Q Rev Biophys. 2006 May;39(2):167-201. Epub 2006 Sep 18. Review.

Lansbury PT, Lashuel HA. A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature. 2006 Oct 19;443(7113):774-9. Review.