In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3

Maria do Carmo Costa, Maria Radzwion, Hayley S. McLoughlin, Naila S. Ashraf, Svetlana Fischer, Vikram G. Shakkottai, Patrícia Maciel, Henry L. Paulson, Gülin Öz

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1 Scopus citations


Background: No treatment exists for the most common dominantly inherited ataxia Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3). Successful evaluation of candidate therapeutics will be facilitated by validated noninvasive biomarkers of disease pathology recapitulated by animal models. Objective: We sought to identify shared in vivo neurochemical signatures in two mouse models of SCA3 that reflect the human disease pathology. Methods: Cerebellar neurochemical concentrations in homozygous YACMJD84.2 (Q84/Q84) and hemizygous CMVMJD135 (Q135) mice were measured by in vivo magnetic resonance spectroscopy at 9.4 tesla. To validate the neurochemical biomarkers, levels of neurofilament medium (NFL; indicator of neuroaxonal integrity) and myelin basic protein (MBP; indicator of myelination) were measured in cerebellar lysates from a subset of mice and patients with SCA3. Finally, NFL and MBP levels were measured in the cerebellar extracts of Q84/Q84 mice upon silencing of the mutant ATXN3 gene. Results: Both Q84/Q84 and Q135 mice displayed lower N-acetylaspartate than wild-type littermates, indicating neuroaxonal loss/dysfunction, and lower myo-inositol and total choline, indicating disturbances in phospholipid membrane metabolism and demyelination. Cerebellar NFL and MBP levels were accordingly lower in both models as well as in the cerebellar cortex of patients with SCA3 than controls. Importantly, N-acetylaspartate and total choline correlated with NFL and MPB, respectively, in Q135 mice. Long-term sustained RNA interference (RNAi)-mediated reduction of ATXN3 levels increased NFL and MBP in Q84/Q84 cerebella. Conclusions: N-acetylaspartate, myo-inositol, and total choline levels in the cerebellum are candidate biomarkers of neuroaxonal and oligodendrocyte pathology in SCA3, aspects of pathology that are reversible by RNAi therapy.

Original languageEnglish (US)
Pages (from-to)1774-1786
Number of pages13
JournalMovement Disorders
Issue number10
StatePublished - Oct 1 2020

Bibliographical note

Funding Information:
The authors thank Dr. Sujith V. Weerasinghe and Dr. M. Bishr Omary for help with the liver studies, the Michigan Brain Bank (5P30 AG053760 University of Michigan Alzheimer's Disease Core Center) and its coordinator Mathew Perkins for providing brain samples of Machado-Joseph disease patients and control individuals, and Dr. Lynn Eberly for statistical consulting. This work was funded by Portuguese National funds through the Foundation for Science and Technology projects UIDB/50026/2020 and PTDC/NEU-NMC/3648/2014, FEDERfunds through the Competitiveness Factors Operational Programme and the Northern Portugal Regional Operational Program (NORTE 2020) under the Portugal 2020 Partnership Agreement (projects NORTE-01-0145-FEDER-000013 and POCI-01-0145-FEDER-016818 to P.M., the National Institutes of Health/National Institute of Neurological Disorders and Stroke R01NS03871 to H.L.P., and National Institutes of Health/ National Institute of Neurological Disorders and Stroke R21 NS111154 to H.S.M. and G.?., and a Becky Babcox Research Fund pilot research award, University of Michigan, to M.C.C. The Center for Magnetic Resonance Research is supported by National Institute of Biomedical Imaging and Bioengineering Grant P41 EB027061, the Institutional Center Cores for Advanced Neuroimaging Award P30 NS076408, and the W.M. Keck Foundation.


  • Machado-Joseph disease
  • ataxin-3
  • demyelination
  • magnetic resonance spectroscopy
  • polyglutamine

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

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