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

被引：47

作者：

Cariulo, Cristina ^{[1
]}

Azzollini, Lucia ^{[1
]}

Verani, Margherita ^{[1
]}

Martufi, Paola ^{[1
]}

Boggio, Roberto ^{[2
]}

Chiki, Anass ^{[3
]}

Deguire, Sean M. ^{[3
]}

Cherubini, Marta ^{[4
,5
]}

Gines, Silvia ^{[4
,5
]}

Marsh, J. Lawrence ^{[6
]}

Conforti, Paola ^{[7
,8
]}

Cattaneo, Elena ^{[7
,8
]}

Santimone, Iolanda ^{[9
]}

Squitieri, Ferdinando ^{[9
]}

Lashuel, Hilal A. ^{[3
]}

Petricca, Lara ^{[1
]}

Caricasole, Andrea ^{[1
]}

机构：

[1] Dept Neurosci, IRBM Sci Pk, I-00071 Rome, Italy

[2] IRBM Promidis, I-00071 Rome, Italy

[3] Ecole Polytech Fed Lausanne, Sch Life Sci, Brain Mind Inst, Lab Mol & Chem Biol Neurodegenerat, CH-1015 Lausanne, Switzerland

[4] Univ Barcelona, Inst Neurociencias, Fac Med, Dept Biomed, Barcelona 08035, Spain

[5] IDIBAPS, Barcelona 08036, Spain

[6] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92697 USA

[7] Univ Milan, Dept Biosci, Lab Stem Cell Biol & Pharmacol Neurodegenerat Dis, I-20122 Milan, Italy

[8] Ist Nazl Genet Mol INGM Romeo & Enrica Invernizzi, I-20122 Milan, Italy

[9] Ist Ricovero & Cura Carattere Sci IRCCS Casa Soll, Huntington & Rare Dis Unit, I-71013 San Giovanni Rotondo, Italy

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 50期

关键词：

huntingtin; posttranslational modification; immunoassay; phosphorylation; neurodegeneration;

D O I：

10.1073/pnas.1705372114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：E10809 / E10818

页数：10

共 3 条

[1] Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons [J].