期刊
MOVEMENT DISORDERS
卷 35, 期 10, 页码 1774-1786出版社
WILEY
DOI: 10.1002/mds.28140
关键词
ataxin-3; demyelination; Machado-Joseph disease; magnetic resonance spectroscopy; polyglutamine
资金
- Michigan Brain Bank (University of Michigan Alzheimer's Disease Core Center) [5P30 AG053760]
- Foundation for Science and Technology [UIDB/50026/2020, PTDC/NEU-NMC/3648/2014]
- FEDERfunds through the Competitiveness Factors Operational Programme
- Northern Portugal Regional Operational Program (NORTE 2020) under the Portugal 2020 Partnership Agreement [NORTE-01-0145FEDER-000013, POCI-01-0145-FEDER-016818]
- National Institutes of Health/National Institute of Neurological Disorders and Stroke [R01NS03871, R21 NS111154]
- Becky Babcox Research Fund pilot research award, University of Michigan
- National Institute of Biomedical Imaging and Bioengineering [P41 EB027061]
- Institutional Center Cores for Advanced Neuroimaging Award [P30 NS076408]
- W.M. Keck Foundation
- Fundação para a Ciência e a Tecnologia [PTDC/NEU-NMC/3648/2014] Funding Source: FCT
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 mutantATXN3gene. Results Both Q84/Q84 and Q135 mice displayed lowerN-acetylaspartate than wild-type littermates, indicating neuroaxonal loss/dysfunction, and lowermyo-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 ofATXN3levels 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. (c) 2020 International Parkinson and Movement Disorder Society
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据