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Biochem Biophys Res Commun. 2016 Sep 16;478(2):949-55. doi: 10.1016/j.bbrc.2016.08.057. Epub 2016 Aug 9.

Conformational modulation mediated by polyglutamine expansion in CAG repeat expansion disease-associated proteins.

Author information

1
IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.
2
IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.
3
IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy.
4
CHDI Management/CHDI Foundation, Los Angeles, CA, 90045, USA.
5
IRBM Promidis, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy; IRBM Science Park, Via Pontina km 30.600, 00071, Pomezia, Rome, Italy. Electronic address: a.caricasole@irbm.it.

Abstract

We have previously reported TR-FRET based immunoassays to detect a conformational change imparted on huntingtin protein by the polyglutamine expansion, which we confirmed using biophysical methodologies. Using these immunoassays, we now report that polyglutamine expansion influences the conformational properties of other polyglutamine disease proteins, exemplified by the androgen receptor (associated with spinal bulbar muscular atrophy) and TATA binding protein (associated with spinocerebellar ataxia 17). Using artificial constructs bearing short or long polyglutamine expansions or a multimerized, unrelated epitope (mimicking the increase in anti-polyglutamine antibody epitopes present in polyglutamine repeats of increasing length) we confirmed that the conformational TR-FRET based immunoassay detects an intrinsic conformational property of polyglutamine repeats. The TR-FRET based conformational immunoassay may represent a rapid, scalable tool to identify modulators of polyglutamine-mediated conformational change in different proteins associated with CAG triplet repeat disorders.

KEYWORDS:

CAG repeat; Conformation; Huntingtin; Neurodegeneration; Polyglutamine; TR–FRET assay

PMID:
27520369
DOI:
10.1016/j.bbrc.2016.08.057
[Indexed for MEDLINE]

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