In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3.
In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3.
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DOI：
10.1002/mds.28140
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Öz G
中科院分区：
文献类型：
--
作者：
Costa MDC;Radzwion M;McLoughlin HS;Ashraf NS;Fischer S;Shakkottai VG;Maciel P;Paulson HL;Öz G
对于最常见的显性遗传性共济失调Machado-Joseph病或脊髓小脑共济失调3型（SCA 3），目前还没有治疗方法。通过动物模型重现的疾病病理学的经验证的非侵入性生物标志物将促进候选治疗剂的成功评价。我们试图在反映人类疾病病理学的SCA 3的两种小鼠模型中鉴定共有的体内神经化学特征。在9.4特斯拉下，通过体内磁共振波谱测量纯合YACMJD 84.2（Q84/Q84）和半合CMVMJD 135（Q135）小鼠的小脑神经化学物质浓度。为了验证神经化学生物标志物，在来自患有SCA 3的小鼠和患者的子集的小脑裂解物中测量神经丝介质（NFL，神经轴突完整性的指示物）和髓鞘碱性蛋白（MBP，髓鞘形成的指示物）的水平。最后，在突变体ATXN 3基因沉默后，在Q84/Q84小鼠的小脑提取物中测量NFL和MBP水平。Q84/Q84和Q135小鼠均显示出比野生型同窝小鼠更低的N-乙酰天冬氨酸，表明神经轴突损失/功能障碍，以及更低的肌醇和总胆碱，表明磷脂膜代谢和脱髓鞘紊乱。小脑NFL和MBP水平在两种模型中相应地较低，以及在SCA 3患者的小脑皮质中比对照组低。重要的是，在Q135小鼠中，N-乙酰天冬氨酸和总胆碱分别与NFL和MPB相关。长期持续RNAi介导的ATXN 3水平降低增加了Q84/Q84小脑中的NFL和MBP。小脑中的N-乙酰天冬氨酸、肌醇和总胆碱水平是SCA 3中神经轴突和少突胶质细胞病理学的候选生物标志物，这些病理学方面通过RNAi疗法是可逆的。
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. We sought to identify shared in vivo neurochemical signatures in two mouse models of SCA3 that reflect the human disease pathology. 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 cerebellar extracts of Q84/Q84 mice upon silencing of the mutant ATXN3 gene. 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 RNAi-mediated reduction of ATXN3 levels increased NFL and MBP in Q84/Q84 cerebella. 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.
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影响因子：
5.1
作者：
Esteves, Sofia;Oliveira, Stephanie;Maciel, Patricia
通讯作者：
Maciel, Patricia
影响因子：
2.2
作者：
Garwood, M;DelaBarre, L
通讯作者：
DelaBarre, L
影响因子：
2.4
作者：
D'Abreu, Anelyssa;Franca, Marcondes C., Jr.;Cendes, Fernando
通讯作者：
Cendes, Fernando
脊椎小脑共济失调：治疗开发的前景和挑战。
DOI：
10.1038/s41582-018-0051-6
发表时间：
2018-10
期刊：
Nature reviews. Neurology
影响因子：
--
作者：
Ashizawa T;Öz G;Paulson HL
通讯作者：
Paulson HL
影响因子：
4.7
作者：
Emir UE;Brent Clark H;Vollmers ML;Eberly LE;Öz G
通讯作者：
Öz G