Research Topics
Genomes and GenesSpecies | Peter LansburySummaryAffiliation: Harvard University Country: USA Publications
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Publications
Genetics of Parkinson's disease and biochemical studies of implicated gene productsPeter T Lansbury
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, Cambridge, Massachusetts 02139, USA
Curr Opin Cell Biol 14:653-60. 2002..Genetic information may prove to be useful in identifying new therapeutic targets and identifying the preclinical phase of PD, allowing treatment to begin sooner...- Genetics of Parkinson's disease and biochemical studies of implicated gene productsPeter T Lansbury
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Curr Opin Genet Dev 12:299-306. 2002..Genetic information may prove to be useful in identifying new therapeutic targets and identifying the preclinical phase of PD, allowing treatment to begin sooner... - Back to the future: the 'old-fashioned' way to new medications for neurodegenerationPeter T Lansbury
Harvard Center for Neurodegeneration and Repair and the Department of Neurology, Harvard Medical School, Center for Neurologic Diseases, Brigham and Women s Hospital, 65 Landsdowne St, Cambridge, Massachusetts 02139, USA
Nat Med 10:S51-7. 2004..Why is this, and what can be done to accelerate it? There are a number of obstacles to effective drug discovery for neurodegeneration, but by considering these problems it is possible to identify lessons for the future... - The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibilityYichin Liu
Center for Neurologic Diseases, Brigham and Women s Hospital, Department of Neurology, Harvard Medical School, Cambridge, MA 02139, USA
Cell 111:209-18. 2002..Thus, the ligase activity as well as the hydrolase activity of UCH-L1 may play a role in proteasomal protein degradation, a critical process for neuronal health... - Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregationSoumya S Ray
Harvard Center for Neurodegeneration and Repair and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
Proc Natl Acad Sci U S A 102:3639-44. 2005..In the presence of several of these molecules, A4V and other FALS-linked SOD1 mutants such as G93A and G85R behaved similarly to wild-type SOD1, suggesting that these compounds could be leads toward effective therapeutics against FALS... - An intersubunit disulfide bond prevents in vitro aggregation of a superoxide dismutase-1 mutant linked to familial amytrophic lateral sclerosisSoumya S Ray
Harvard Center for Neurodegeneration and Repair and Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA
Biochemistry 43:4899-905. 2004..A drug-like molecule that could stabilize the A4V dimer could slow the onset and progression of FALS... - A computer program for the estimation of protein and nucleic acid sequence diversity in random point mutagenesis librariesMichael J Volles
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School 65 Landsdowne Street, Cambridge, MA 02139, USA
Nucleic Acids Res 33:3667-77. 2005..Estimators of DNA polymerase mutation-type-specific error rates are derived using the model. Analyses of an alpha-synuclein ep-PCR library and NNS synthetic oligonucleotide libraries are given as examples... - A century-old debate on protein aggregation and neurodegeneration enters the clinicPeter T Lansbury
Department of Neurology, Harvard Medical School and Brigham and Women s Hospital, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Nature 443:774-9. 2006..The clinical trials could also settle the century-old debate about causality... - Relationships between the sequence of alpha-synuclein and its membrane affinity, fibrillization propensity, and yeast toxicityMichael J Volles
Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
J Mol Biol 366:1510-22. 2007..We hypothesize that yeast toxicity is caused by synuclein binding directly to membranes at levels sufficient to non-specifically disrupt homeostasis... - Improving binding specificity of pharmacological chaperones that target mutant superoxide dismutase-1 linked to familial amyotrophic lateral sclerosis using computational methodsRichard J Nowak
Harvard NeuroDiscovery Center, Harvard Medical School, Boston, Massachusetts, USA
J Med Chem 53:2709-18. 2010..At least six of the new molecules exhibited high specificity of binding toward SOD-1 in the presence of blood plasma. These molecules represent a new class of molecules for further development into clinical candidates... - Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's diseaseMichael J Volles
Center for Neurologic Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 42:7871-8. 2003..Toxicity may arise from pore-like protofibrils that cause membrane permeabilization. An approach to testing this hypothesis is discussed... - Neurodegenerative disease: amyloid pores from pathogenic mutationsHilal A Lashuel
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Nature 418:291. 2002.... - The N-terminal repeat domain of alpha-synuclein inhibits beta-sheet and amyloid fibril formationJeffrey C Kessler
Center for Neurologic Diseases, Brigham and Women s Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 42:672-8. 2003..N-terminal truncation of alpha-synuclein may promote pathogenesis... - Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson's diseaseJune Young Park
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 42:3696-700. 2003..Significantly, beta-synuclein inhibits the generation of A53T alpha-synuclein protofibrils and fibrils. This finding provides a rationale for the phenotype of the double-transgenic mice and suggests a therapeutic strategy for PD... - Improving synaptic function in a mouse model of ADPeter T Lansbury
Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA
Cell 126:655-7. 2006..This work also raises the question of what role UCH-L1 might play in other diseases involving protein aggregation, such as Parkinson's Disease... - The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric statesRoss A Fredenburg
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 46:7107-18. 2007.... - A possible therapeutic target for Lou Gehrig's diseaseSoumya S Ray
Center for Neurologic Diseases, Brigham and Women's Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA
Proc Natl Acad Sci U S A 101:5701-2. 2004 - Substrate recognition and catalysis by UCH-L1Sarah J Luchansky
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital and Laboratory for Drug Discovery in Neurodegeneration, Harvard Center for Neurodegeneration and Repair, Cambridge, Massachusetts 02139, USA
Biochemistry 45:14717-25. 2006..These data provide dramatic examples of differences in substrate specificity between these enzymes. The implications of our experiments with UCH-L1 for selective inhibitor design and the relationship to disease are discussed... - Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanismMichael J Volles
Center for Neurologic Diseases, Brigham and Women s Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 41:4595-602. 2002..We conclude that the pathogenesis of Parkinson's disease may involve membrane permeabilization by protofibrillar alpha-synuclein, the extent of which will be strongly dependent on the in vivo conditions... - Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1Robin K Meray
Department of Neurology, Harvard Medical School and Brigham and Women s Hospital, Cambridge, Massachusetts 02139, USA
J Biol Chem 282:10567-75. 2007..Our results illustrate monoubiquitination as a reversible regulatory mechanism for DUB activity involving auto-deubiquitination... - Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrilsHilal A Lashuel
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, Cambridge, MA 02139, USA
J Mol Biol 322:1089-102. 2002..The formation of pore-like oligomeric structures may explain the membrane permeabilization activity of alpha-synuclein protofibrils. These structures may contribute to the pathogenesis of PD... - Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's diseaseJean Christophe Rochet
Center for Neurologic Diseases, Brigham and Women s Hospital, Department of Neurology, Harvard Medical School, Cambridge, MA 02139, USA
J Mol Neurosci 23:23-34. 2004..These variants might be useful to test whether membrane binding by alpha-synuclein is necessary for neurodegeneration in transgenic animal models of PD... - Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's diseaseZhihua Liu
Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA
Proc Natl Acad Sci U S A 106:4635-40. 2009..Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies... - Molecular crowding accelerates fibrillization of alpha-synuclein: could an increase in the cytoplasmic protein concentration induce Parkinson's disease?Mark D Shtilerman
Center for Neurologic Diseases, Brigham and Women s Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 41:3855-60. 2002..Thus, nonspecific changes in the total cytoplasmic protein concentration, induced by cell volume changes and/or altered protein degradation, could promote formation of and stabilize the alpha-synuclein protofibril... - Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetesMagdalena Anguiano
Center for Neurologic Diseases, Brigham and Women's Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 41:11338-43. 2002..Neither pores nor oligomers were formed by the nonfibrillogenic rat IAPP variant. The IAPP amyloid pore may be critical to the pathogenic mechanism of NIDDM, as other amyloid pores may be to Alzheimer's disease and Parkinson's disease... - Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranesTomas T Ding
Center for Neurologic Diseases, Brigham and Women s Hospital, and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, Massachusetts 02139, USA
Biochemistry 41:10209-17. 2002..Thus, abnormal membrane permeabilization may be a pathogenic mechanism in PD... - Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell lineYichin Liu
Center for Neurologic Diseases, Brigham and Women's Hospital, 65 Landsdowne Street, Cambridge, MA 02139, USA
Chem Biol 10:837-46. 2003..The molecular mechanism of this response remains to be determined... - Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid poresHilal A Lashuel
Harvard Center for Neurodegeneration and Repair, 65 Landsdowne St, Cambridge, MA 02139, USA
J Mol Biol 332:795-808. 2003..An increase in the ratio of Abeta(WT)/Abeta(MUT(Arctic)), therefore, may result in the accumulation of potential neurotoxic protofibrils and acceleration of disease progression in familial Alzheimer's disease mutation carriers... - Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?Hilal A Lashuel
Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, CH 1015 Lausanne, Switzerland
Q Rev Biophys 39:167-201. 2006..The purpose of this review is to summarize the existing supportive circumstantial evidence and to stimulate further studies designed to test the validity of this hypothesis... - Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1Chittaranjan Das
Department of Chemistry and Biochemistry, Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, MA 02454 9110, USA
Proc Natl Acad Sci U S A 103:4675-80. 2006..In particular, the geometry of the catalytic residues in the active site of UCH-L1 is distorted in such a way that the hydrolytic activity would appear to be impossible without substrate induced conformational rearrangements... - Your health in the 21st century. A fix for faulty proteinsPeter T Lansbury
Newsweek 145:52. 2005 - Dissociation of amyloid fibrils of alpha-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavitiesDebora Foguel
Departamento de Bioquimica Medica, Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 21941 590, Brazil
Proc Natl Acad Sci U S A 100:9831-6. 2003..Finally, the HHP-induced formation of fibrils from TTR is relatively fast (approximately 60 min), a quality that allows screening of antiamyloidogenic drugs... - Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystandersByron Caughey
NIAID, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA
Annu Rev Neurosci 26:267-98. 2003..This review focuses on recent experimental studies aimed at identification and characterization of the neurotoxic protein aggregates... - Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagyAna Maria Cuervo
Department of Anatomy and Structural Biology, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Science 305:1292-5. 2004..These findings may underlie the toxic gain-of-function by the mutants... - Abeta protofibrils possess a stable core structure resistant to hydrogen exchangeIndu Kheterpal
Graduate School of Medicine, University of Tennessee, 1924 Alcoa Highway, Knoxville, Tennessee 37920, USA
Biochemistry 42:14092-8. 2003..These and other data are interpreted and discussed in terms of the role of protofibrils in fibril assembly and in disease... - Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagyMarta Martinez-Vicente
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Yeshiva University, New York, New York 10461, USA
J Clin Invest 118:777-88. 2008..As blockage of CMA increases cellular vulnerability to stressors, we propose that dopamine-induced autophagic inhibition could explain the selective degeneration of PD dopaminergic neurons... - Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synucleinKaterina E Paleologou
Laboratory of Molecular Neurobiology and Neuroproteomics, Brain Mind Institute, Ecole Polytechnique Federale de Lausanne, CH 1015 Lausanne, Switzerland
J Biol Chem 283:16895-905. 2008....
Research Grants
- A High-Throughput Assay-SOD1 Aggregation Inhibitors(RMI)Peter Lansbury; Fiscal Year: 2005..Our ultimate goal is to identify candidates that justify filing for IND status. ..
- Discovery of highly toxic synuclein sequence variantsPeter Lansbury; Fiscal Year: 2006....
- High Throughout Assay to Probe UCH-L1 Ligase InhibitorsPeter Lansbury; Fiscal Year: 2005..The program detailed below will seek probes with the following activities: (1) inhibitors ofUCH-L1 dimerization, (2) inhibitors of UCH-L1 ligase activity, and (3) repressors and activators of UCH-L1 expression. ..
- Amyloid Deposition in Alzheimer's and Related DiseasesPeter Lansbury; Fiscal Year: 2005..Finally, we will investigate one possible mechanism by which protofibrils could lead to cell death, that is, inappropriate and uncontrolled membrane permeabilization. ..
- AMYLOID DEPOSITION IN ALZHEIMER'S DISEASEPeter Lansbury; Fiscal Year: 2000..Finally, it is hoped that the research will lead to the design of molecules that act as inhibitors of amyloid formation. The structure of these molecules will derive from the ongoing studies of amyloid structure. ..