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

Abstract

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. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Authors: Jeannette Hübener-Schmid, Kirsten Kuhlbrodt, Julien Peladan, Jennifer Faber, Magda M Santana, Holger Hengel, Heike Jacobi, Kathrin Reetz, Hector Garcia-Moreno, Mafalda Raposo, Judith van Gaalen, Jon Infante, Katharina M Steiner, Jeroen de Vries, Marcel M Verbeek, Paola Giunti, Luis Pereira de Almeida, Manuela Lima, Bart van de Warrenburg, Ludger Schöls, Thomas Klockgether, Matthis Synofzik, European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI) Study Group, Olaf Riess
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 36 Issue 11 Pg. 2675-2681 (11 2021) ISSN: 1531-8257 [Electronic] United States
• PMID: 34397117 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Chemical References

• Peptides
• polyglutamine
• Ataxin-3

Topics

• Ataxin-3 (genetics)
• Cross-Sectional Studies
• Humans
• Machado-Joseph Disease (drug therapy, genetics)
• Neurodegenerative Diseases
• Peptides