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Phosphorylation of huntingtin at residue T3 is decreased in Huntington's disease and modulates mutant huntingtin protein conformation.

  • Cariulo C Department of Neuroscience, IRBM Science Park, 00071 Pomezia, Rome, Italy.
  • Azzollini L Department of Neuroscience, IRBM Science Park, 00071 Pomezia, Rome, Italy.
  • Verani M Department of Neuroscience, IRBM Science Park, 00071 Pomezia, Rome, Italy.
  • Martufi P Department of Neuroscience, IRBM Science Park, 00071 Pomezia, Rome, Italy.
  • Boggio R IRBM Promidis, 00071 Pomezia, Rome, Italy.
  • Chiki A Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
  • Deguire SM Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
  • Cherubini M Departamento de Biomedicina, Facultad de Medicina, Instituto de Neurociencias, Universidad de Barcelona, 08035 Barcelona, Spain.
  • Gines S Departamento de Biomedicina, Facultad de Medicina, Instituto de Neurociencias, Universidad de Barcelona, 08035 Barcelona, Spain.
  • Marsh JL Department of Developmental and Cell Biology, University of California, Irvine, CA 92697.
  • Conforti P Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122 Milan, Italy.
  • Cattaneo E Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122 Milan, Italy.
  • Santimone I Huntington and Rare Diseases Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
  • Squitieri F Huntington and Rare Diseases Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy.
  • Lashuel HA Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; hilal.lashuel@epfl.ch l.petricca@irbm.it a.caricasole@irbm.it.
  • Petricca L Department of Neuroscience, IRBM Science Park, 00071 Pomezia, Rome, Italy; hilal.lashuel@epfl.ch l.petricca@irbm.it a.caricasole@irbm.it.
  • Caricasole A Department of Neuroscience, IRBM Science Park, 00071 Pomezia, Rome, Italy; hilal.lashuel@epfl.ch l.petricca@irbm.it a.caricasole@irbm.it.
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  • 2017-11-23
Published in:
  • Proceedings of the National Academy of Sciences of the United States of America. - 2017
huntingtin
immunoassay
neurodegeneration
phosphorylation
posttranslational modification
Animals
Cells, Cultured
Exons
HEK293 Cells
Humans
Huntingtin Protein
Huntington Disease
Immunoassay
Mice
Mutant Proteins
Phosphorylation
Protein Conformation
Protein Processing, Post-Translational
Sensitivity and Specificity
English Posttranslational modifications can have profound effects on the biological and biophysical properties of proteins associated with misfolding and aggregation. However, their detection and quantification in clinical samples and an understanding of the mechanisms underlying the pathological properties of misfolding- and aggregation-prone proteins remain a challenge for diagnostics and therapeutics development. We have applied an ultrasensitive immunoassay platform to develop and validate a quantitative assay for detecting a posttranslational modification (phosphorylation at residue T3) of a protein associated with polyglutamine repeat expansion, namely Huntingtin, and characterized its presence in a variety of preclinical and clinical samples. We find that T3 phosphorylation is greatly reduced in samples from Huntington's disease models and in Huntington's disease patients, and we provide evidence that bona-fide T3 phosphorylation alters Huntingtin exon 1 protein conformation and aggregation properties. These findings have significant implications for both mechanisms of disease pathogenesis and the development of therapeutics and diagnostics for Huntington's disease.
Language
  • English
Open access status
hybrid
Identifiers
Persistent URL
https://sonar.ch/global/documents/102645
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