Help Privacy Policy Disclaimer
  Advanced SearchBrowse


  Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation

Sen, N.-E., Canet-Pons, J., Halbach, M. V., Arsovic, A., Pilatus, U., Chae, W.-H., et al. (2019). Generation of an Atxn2-CAG100 knock-in mouse reveals N-acetylaspartate production deficit due to early Nat8l dysregulation. Neurobiology of Disease, 132: 104559. doi:10.1016/j.nbd.2019.104559.

Item is


show Files




Sen, Nesli-Ece , Author
Canet-Pons, Júlia , Author
Halbach, Melanie V. , Author
Arsovic, Aleksandar , Author
Pilatus, Ulrich , Author
Chae, Woon-Hyung , Author
Kaya, Zeynep-Ece , Author
Seidel, Kay , Author
Rollmann, Ewa , Author
Mittelbronn, Michel , Author
Meierhofer, David1, Author           
De Zeeuw, Chris I. , Author
Bosman, Laurens W. J. , Author
Gispert, Suzana , Author
Auburger, Georg , Author
1Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479669              


Free keywords: Mitochondrial bioenergetics; Molecular biomarkers of disease; N-acetylaspartate; Polyglutamine expansion; RNA processing; Stress granules
 Abstract: Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder caused by CAG-expansion mutations in the ATXN2 gene, mainly affecting motor neurons in the spinal cord and Purkinje neurons in the cerebellum. While the large expansions were shown to cause SCA2, the intermediate length expansions lead to increased risk for several atrophic processes including amyotrophic lateral sclerosis and Parkinson variants, e.g. progressive supranuclear palsy. Intense efforts to pioneer a neuroprotective therapy for SCA2 require longitudinal monitoring of patients and identification of crucial molecular pathways. The ataxin-2 (ATXN2) protein is mainly involved in RNA translation control and regulation of nutrient metabolism during stress periods. The preferential mRNA targets of ATXN2 are yet to be determined. In order to understand the molecular disease mechanism throughout different prognostic stages, we generated an Atxn2-CAG100-knock-in (KIN) mouse model of SCA2 with intact murine ATXN2 expression regulation. Its characterization revealed somatic mosaicism of the expansion, with shortened lifespan, a progressive spatio-temporal pattern of pathology with subsequent phenotypes, and anomalies of brain metabolites such as N-acetylaspartate (NAA), all of which mirror faithfully the findings in SCA2 patients. Novel molecular analyses from stages before the onset of motor deficits revealed a strong selective effect of ATXN2 on Nat8l mRNA which encodes the enzyme responsible for NAA synthesis. This metabolite is a prominent energy store of the brain and a well-established marker for neuronal health. Overall, we present a novel authentic rodent model of SCA2, where in vivo magnetic resonance imaging was feasible to monitor progression and where the definition of earliest transcriptional abnormalities was possible. We believe that this model will not only reveal crucial insights regarding the pathomechanism of SCA2 and other ATXN2-associated disorders, but will also aid in developing gene-targeted therapies and disease prevention.


Language(s): eng - English
 Dates: 2019-07-302019-07-31
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1016/j.nbd.2019.104559
PMID: 31376479
 Degree: -



Legal Case


Project information


Source 1

Title: Neurobiology of Disease
  Other : Neurobiol. Dis.
Source Genre: Journal
Publ. Info: Oxford : Academic Press
Pages: - Volume / Issue: 132 Sequence Number: 104559 Start / End Page: - Identifier: ISSN: 0969-9961
CoNE: https://pure.mpg.de/cone/journals/resource/954922649144