Polyglutamine-Expanded Ataxin-3: A Target Engagement Marker for Spinocerebellar Ataxia Type 3 in Peripheral Blood

被引：19

作者：

Huebener-Schmid, Jeannette ^{[1
,2
]}

Kuhlbrodt, Kirsten ^{[3
]}

Peladan, Julien ^{[3
]}

Faber, Jennifer ^{[4
,5
]}

Santana, Magda M. ^{[6
,7
,8
]}

Hengel, Holger ^{[9
,10
,11
]}

Jacobi, Heike ^{[12
]}

Reetz, Kathrin ^{[13
,14
]}

Garcia-Moreno, Hector ^{[15
,16
]}

Raposo, Mafalda ^{[17
,18
]}

van Gaalen, Judith ^{[19
]}

Infante, Jon ^{[20
]}

Steiner, Katharina M. ^{[21
]}

de Vries, Jeroen ^{[22
]}

Verbeek, Marcel M. ^{[19
,23
]}

Giunti, Paola ^{[15
,16
]}

Pereira de Almeida, Luis ^{[6
,7
,8
,24
]}

Lima, Manuela ^{[17
,18
]}

van de Warrenburg, Bart ^{[19
]}

Schoels, Ludger ^{[9
,10
,11
]}

Klockgether, Thomas ^{[4
,5
]}

Synofzik, Matthis ^{[9
,10
,11
]}

Riess, Olaf

机构：

[1] Univ Tubingen, Inst Med Genet & Appl Genom, Nagelestr 5, D-72074 Tubingen, Germany

[2] Univ Tubingen, Ctr Rare Dis, Tubingen, Germany

[3] Evotec SE, Hamburg, Germany

[4] German Ctr Neurodegenerat Dis, DZNE, Bonn, Germany

[5] Univ Hosp Bonn, Dept Neurol, Bonn, Germany

[6] Univ Coimbra, Ctr Neurosci & Cell Biol CNC, Coimbra, Portugal

[7] Univ Coimbra, Ctr Innovat Biomed & Biotechnol CIBB, Coimbra, Portugal

[8] Univ Coimbra, IIIUC Inst Interdisciplinary Res, Coimbra, Portugal

[9] Univ Tubingen, Dept Neurodegenerat Dis, Tubingen, Germany

[10] Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany

[11] German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany

[12] Univ Heidelberg Hosp, Dept Neurol, Heidelberg, Germany

[13] Rhein Westfal TH Aachen, Dept Neurol, Aachen, Germany

[14] JARA Brain Inst Mol Neurosci & Neuroimaging, Julich, Germany

[15] UCL, UCL Queen Sq Inst Neurol, Ataxia Ctr, Dept Clin & Movement Neurosci, London, England

[16] Univ Coll London Hosp NHS Fdn Trust, Natl Hosp Neurol & Neurosurg, Dept Neurogenet, London, England

[17] Univ Acores, Fac Ciencias & Tecnol, Ponta Delgada, Portugal

[18] Univ Porto, Inst Investigacao & Inovacao Saude i3S, Inst Biol Mol & Celular IBMC, Porto, Portugal

[19] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands

[20] Univ Cantabria UC, Univ Hosp Marques Valdecilla IDIVAL, Serv Neurol, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Santander, Spain

[21] Univ Duisburg Essen, Essen Univ Hosp, Ctr Translat Neuro & Behav Sci, Dept Neurol, Essen, Germany

[22] Univ Groningen, Univ Med Ctr Groningen, Dept Neurol, Groningen, Netherlands

[23] Radboud Univ Nijmegen, Med Ctr, Dept Lab Med, Nijmegen, Netherlands

[24] Univ Coimbra, Fac Pharm, Coimbra, Portugal

来源：

MOVEMENT DISORDERS | 2021年 / 36卷 / 11期

基金：

英国医学研究理事会; 美国国家卫生研究院; 欧盟地平线“2020”;

关键词：

ataxin-3; Machado-Joseph disease; spinocerebellar ataxia type 3; singulex technology; target engagement biomarker;

D O I：

10.1002/mds.28749

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Background Spinocerebellar ataxia type 3 is a rare neurodegenerative disease caused by a CAG repeat expansion in the ataxin-3 gene. Although no curative therapy is yet available, preclinical gene-silencing approaches to reduce polyglutamine (polyQ) toxicity demonstrate promising results. In view of upcoming clinical trials, quantitative and easily accessible molecular markers are of critical importance as pharmacodynamic and particularly as target engagement markers. Objective We aimed at developing an ultrasensitive immunoassay to measure specifically polyQ-expanded ataxin-3 in plasma and cerebrospinal fluid (CSF). Methods Using the novel single molecule counting ataxin-3 immunoassay, we analyzed cross-sectional and longitudinal patient biomaterials. Results Statistical analyses revealed a correlation with clinical parameters and a stability of polyQ-expanded ataxin-3 during conversion from the pre-ataxic to the ataxic phases. Conclusions The novel immunoassay is able to quantify polyQ-expanded ataxin-3 in plasma and CSF, whereas ataxin-3 levels in plasma correlate with disease severity. Longitudinal analyses demonstrated a high stability of polyQ-expanded ataxin-3 over a short period. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

引用

页码：2675 / 2681

页数：7

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