Peter T Lansbury

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. pmc A possible therapeutic target for Lou Gehrig's disease
    Soumya 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
  2. pmc Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation
    Soumya 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
  3. ncbi request reprint A century-old debate on protein aggregation and neurodegeneration enters the clinic
    Peter 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
  4. pmc Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease
    Zhihua 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
  5. ncbi request reprint The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states
    Ross 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
  6. ncbi request reprint Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores
    Hilal A Lashuel
    Harvard Center for Neurodegeneration and Repair, 65 Landsdowne St, Cambridge, MA 02139, USA
    J Mol Biol 332:795-808. 2003
  7. ncbi request reprint Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils
    Hilal 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
  8. pmc Relationships between the sequence of alpha-synuclein and its membrane affinity, fibrillization propensity, and yeast toxicity
    Michael 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
  9. ncbi request reprint The N-terminal repeat domain of alpha-synuclein inhibits beta-sheet and amyloid fibril formation
    Jeffrey 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
  10. ncbi request reprint Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's disease
    Jean 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

Collaborators

Detail Information

Publications37

  1. pmc A possible therapeutic target for Lou Gehrig's disease
    Soumya 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
  2. pmc Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation
    Soumya 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...
  3. ncbi request reprint A century-old debate on protein aggregation and neurodegeneration enters the clinic
    Peter 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...
  4. pmc Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease
    Zhihua 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...
  5. ncbi request reprint The impact of the E46K mutation on the properties of alpha-synuclein in its monomeric and oligomeric states
    Ross 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
    ....
  6. ncbi request reprint Mixtures of wild-type and a pathogenic (E22G) form of Abeta40 in vitro accumulate protofibrils, including amyloid pores
    Hilal 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...
  7. ncbi request reprint Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils
    Hilal 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...
  8. pmc Relationships between the sequence of alpha-synuclein and its membrane affinity, fibrillization propensity, and yeast toxicity
    Michael 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...
  9. ncbi request reprint The N-terminal repeat domain of alpha-synuclein inhibits beta-sheet and amyloid fibril formation
    Jeffrey 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...
  10. ncbi request reprint Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for understanding neurodegeneration in Parkinson's disease
    Jean 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...
  11. ncbi request reprint Substrate recognition and catalysis by UCH-L1
    Sarah 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...
  12. ncbi request reprint The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility
    Yichin 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...
  13. ncbi request reprint Reversible monoubiquitination regulates the Parkinson disease-associated ubiquitin hydrolase UCH-L1
    Robin 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...
  14. ncbi request reprint Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson's disease
    June 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...
  15. pmc The first N-terminal amino acids of alpha-synuclein are essential for alpha-helical structure formation in vitro and membrane binding in yeast
    Katherina Vamvaca
    Center for Neurologic Diseases, Brigham and Women s Hospital and Department of Neurology, Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA
    J Mol Biol 389:413-24. 2009
    ..Variants with distinct structural preferences, identified here by a reductionist approach, provide valuable tools for elucidating the nature of toxic forms of alpha-syn in neurons...
  16. ncbi request reprint Back to the future: the 'old-fashioned' way to new medications for neurodegeneration
    Peter 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...
  17. ncbi request reprint Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line
    Yichin 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...
  18. ncbi request reprint An intersubunit disulfide bond prevents in vitro aggregation of a superoxide dismutase-1 mutant linked to familial amytrophic lateral sclerosis
    Soumya 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...
  19. ncbi request reprint Genetics of Parkinson's disease and biochemical studies of implicated gene products
    Peter 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...
  20. ncbi request reprint Improving synaptic function in a mouse model of AD
    Peter 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...
  21. ncbi request reprint Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson's disease
    Michael 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...
  22. ncbi request reprint Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes
    Magdalena 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...
  23. ncbi request reprint Genetics of Parkinson's disease and biochemical studies of implicated gene products
    Peter 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...
  24. pmc A computer program for the estimation of protein and nucleic acid sequence diversity in random point mutagenesis libraries
    Michael 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...
  25. ncbi request reprint Annular alpha-synuclein protofibrils are produced when spherical protofibrils are incubated in solution or bound to brain-derived membranes
    Tomas 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...
  26. ncbi request reprint Neurodegenerative disease: amyloid pores from pathogenic mutations
    Hilal 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
    ....
  27. ncbi request reprint Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism
    Michael 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...
  28. ncbi request reprint 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...
  29. pmc Structural basis for conformational plasticity of the Parkinson's disease-associated ubiquitin hydrolase UCH-L1
    Chittaranjan 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...
  30. ncbi request reprint Your health in the 21st century. A fix for faulty proteins
    Peter T Lansbury
    Newsweek 145:52. 2005
  31. ncbi request reprint Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders
    Byron 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...
  32. pmc Dissociation of amyloid fibrils of alpha-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavities
    Debora 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...
  33. ncbi request reprint 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...
  34. ncbi request reprint Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy
    Ana 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...
  35. pmc Dopamine-modified alpha-synuclein blocks chaperone-mediated autophagy
    Marta 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...
  36. pmc Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of alpha-synuclein
    Katerina 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
    ....
  37. ncbi request reprint Abeta protofibrils possess a stable core structure resistant to hydrogen exchange
    Indu 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...