Polyglutamine expansion affects huntingtin conformation in multiple Huntington's disease models.

Autor: Daldin M; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Fodale V; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.; IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Cariulo C; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Azzollini L; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.; IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Verani M; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.; IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Martufi P; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Spiezia MC; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Deguire SM; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland., Cherubini M; Departamento de Ciencias Biomedicas, Facultat de Medicina, Instituto de Neurociencias, Universitat de Barcelona, Barcelona, Spain., Macdonald D; CHDI Management/CHDI Foundation, Los Angeles, CA, 90045, USA., Weiss A; IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.; Evotec AG, Manfred Eigen Campus, Hamburg, Germany., Bresciani A; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Vonsattel JG; Taub Institute for Research on Alzheimer's disease and the Aging Brain, Columbia University Medical Center, 710 West 168th Street, New York, NY, 10032, USA., Petricca L; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.; IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy., Marsh JL; Department of Developmental and Cell Biology, University of California, Irvine, 92697, USA., Gines S; Departamento de Ciencias Biomedicas, Facultat de Medicina, Instituto de Neurociencias, Universitat de Barcelona, Barcelona, Spain., Santimone I; Huntington and Rare Diseases Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Marano M; Huntington and Rare Diseases Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Lashuel HA; Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, Station 19, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015, Lausanne, Switzerland., Squitieri F; Huntington and Rare Diseases Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy., Caricasole A; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy. a.caricasole@irbm.it.; IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy. a.caricasole@irbm.it.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2017 Jul 11; Vol. 7 (1), pp. 5070. Date of Electronic Publication: 2017 Jul 11.
DOI: 10.1038/s41598-017-05336-7
Abstrakt: Conformational changes in disease-associated or mutant proteins represent a key pathological aspect of Huntington's disease (HD) and other protein misfolding diseases. Using immunoassays and biophysical approaches, we and others have recently reported that polyglutamine expansion in purified or recombinantly expressed huntingtin (HTT) proteins affects their conformational properties in a manner dependent on both polyglutamine repeat length and temperature but independent of HTT protein fragment length. These findings are consistent with the HD mutation affecting structural aspects of the amino-terminal region of the protein, and support the concept that modulating mutant HTT conformation might provide novel therapeutic and diagnostic opportunities. We now report that the same conformational TR-FRET based immunoassay detects polyglutamine- and temperature-dependent changes on the endogenously expressed HTT protein in peripheral tissues and post-mortem HD brain tissue, as well as in tissues from HD animal models. We also find that these temperature- and polyglutamine-dependent conformational changes are sensitive to bona-fide phosphorylation on S13 and S16 within the N17 domain of HTT. These findings provide key clinical and preclinical relevance to the conformational immunoassay, and provide supportive evidence for its application in the development of therapeutics aimed at correcting the conformation of polyglutamine-expanded proteins as well as the pharmacodynamics readouts to monitor their efficacy in preclinical models and in HD patients.
Databáze: MEDLINE
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