Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis.
Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis.
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DOI：
10.1038/s41598-020-73845-z
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发表时间：
2020-10-07
影响因子：
4.6
通讯作者：
King PH
中科院分区：
文献类型：
--
作者：
Kwan T;Kazamel M;Thoenes K;Si Y;Jiang N;King PH
骨骼肌和神经肌肉接头是肌萎缩侧索硬化（ALS）最早出现病变的部位。基于先前的研究，我们已经确定了肌肉中的分子特征，该分子特征在ALS早期发展并与疾病进展平行。这个信号代表了包括Smads、TGF-β和维生素D在内的信号通路的交叉点。在这里，我们表明，Wnt拮抗剂，卷曲相关蛋白（FRZB），增加ALS肌肉样本和其他去神经病变的程度不同，但只有最低限度地在获得性肌病。在SOD 1G 93 A小鼠中，FRZB在疾病的早期阶段（40至60天）上调，直至终末期。免疫组化结果显示，FRZB主要定位于肌内膜结缔组织，其次为肌膜。萎缩肌纤维周围的免疫反应性显著增加。由于FRZB是Wnt拮抗剂，我们评估了Wnt信号传导的经典转导子β-连环蛋白，发现主要在肌肉膜上水平增加。总之，我们表明FRZB是肌肉去神经支配的分子特征的一部分，可能反映ALS的疾病进展。我们的研究结果开辟了未来的调查，FRZB和Wnt信号可能在肌肉去神经支配/再神经支配中发挥什么作用的途径。
Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signature represents an intersection of signaling pathways including Smads, TGF-β, and vitamin D. Here, we show that the Wnt antagonist, Frizzled Related Protein (FRZB), was increased in ALS muscle samples and to a variable extent other denervating disease but only minimally in acquired myopathies. In the SOD1G93A mouse, FRZB was upregulated in the early stages of disease (between 40 and 60 days) until end-stage. By immunohistochemistry, FRZB was predominantly localized to endomysial connective tissue and to a lesser extent muscle membrane. There was a significant increase in immunoreactivity surrounding atrophied myofibers. Because FRZB is a Wnt antagonist, we assessed β-catenin, the canonical transducer of Wnt signaling, and found increased levels mainly at the muscle membrane. In summary, we show that FRZB is part of a molecular signature of muscle denervation that may reflect disease progression in ALS. Our findings open up avenues for future investigation as to what roles FRZB and Wnt signaling might be playing in muscle denervation/reinnervation.
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DOI：
10.1136/jnnp.2009.183525
发表时间：
2010-04
期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
--
作者：
Logroscino G;Traynor BJ;Hardiman O;Chiò A;Mitchell D;Swingler RJ;Millul A;Benn E;Beghi E;EURALS
通讯作者：
EURALS
影响因子：
4.8
作者：
Hoang, B;Moos, M;Luyten, FP
通讯作者：
Luyten, FP
影响因子：
3.7
作者：
Gonzalez D;Contreras O;Rebolledo DL;Espinoza JP;van Zundert B;Brandan E
通讯作者：
Brandan E
影响因子：
7.1
作者：
Al-Sarraj S;King A;Cleveland M;Pradat PF;Corse A;Rothstein JD;Leigh PN;Abila B;Bates S;Wurthner J;Meininger V
通讯作者：
Meininger V
影响因子：
7.2
作者：
Koles, Kate;Budnik, Vivian
通讯作者：
Budnik, Vivian