Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations.
Brain region-specific susceptibility of Lewy body pathology in synucleinopathies is governed by α-synuclein conformations.
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DOI：
10.1007/s00401-022-02406-7
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发表时间：
2022-04
影响因子：
12.7
通讯作者：
Bartels T
中科院分区：
文献类型：
--
作者：
de Boni L;Watson AH;Zaccagnini L;Wallis A;Zhelcheska K;Kim N;Sanderson J;Jiang H;Martin E;Cantlon A;Rovere M;Liu L;Sylvester M;Lashley T;Dettmer U;Jaunmuktane Z;Bartels T
α-突触核蛋白蛋白是帕金森病（PD）和其他突触核蛋白病的关键参与者，它以不同的生理构象存在：细胞质内易聚集的未折叠单体和螺旋聚集抗性多聚体。研究表明，家族性pd相关的α-突触核蛋白基因错义突变破坏了生理性α-突触核蛋白的构象平衡，有利于未折叠的单体。在这里，我们表征了死后人脑组织中未折叠和螺旋形式的细胞质α-突触核蛋白的相对水平，并表明α-突触核蛋白构象的平衡在散发性PD和DLB患者中不稳定。在患者样本中，这种失调的平衡以脑区域特异性的方式减少，这表明潜在病理可能存在“朊病毒样”传播，并在两种不同的突触核蛋白病中形成不同的疾病特异性模式。我们还能够证明，多聚体的不稳定在机制上导致不溶性的病理性α-突触核蛋白水平增加，而多聚体的药理学稳定导致“朊病毒样”的聚集抗性。总之，我们的研究结果表明，散发性PD和DLB中α-突触核蛋白多片段失稳的这些疾病特异性模式是由局部神经元易感性和局部内源性α-突触核蛋白失稳导致的“朊病毒样”聚集传递引起的。在线版本包含补充资料，网址为10.1007/s00401-022-02406-7。
The protein α-synuclein, a key player in Parkinson’s disease (PD) and other synucleinopathies, exists in different physiological conformations: cytosolic unfolded aggregation-prone monomers and helical aggregation-resistant multimers. It has been shown that familial PD-associated missense mutations within the α-synuclein gene destabilize the conformer equilibrium of physiologic α-synuclein in favor of unfolded monomers. Here, we characterized the relative levels of unfolded and helical forms of cytosolic α-synuclein in post-mortem human brain tissue and showed that the equilibrium of α-synuclein conformations is destabilized in sporadic PD and DLB patients. This disturbed equilibrium is decreased in a brain region-specific manner in patient samples pointing toward a possible “prion-like” propagation of the underlying pathology and forms distinct disease-specific patterns in the two different synucleinopathies. We are also able to show that a destabilization of multimers mechanistically leads to increased levels of insoluble, pathological α-synuclein, while pharmacological stabilization of multimers leads to a “prion-like” aggregation resistance. Together, our findings suggest that these disease-specific patterns of α-synuclein multimer destabilization in sporadic PD and DLB are caused by both regional neuronal vulnerability and “prion-like” aggregation transmission enabled by the destabilization of local endogenous α-synuclein protein. The online version contains supplementary material available at 10.1007/s00401-022-02406-7.
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影响因子：
5.5
作者：
Angelova DM;Brown DR
通讯作者：
Brown DR
影响因子：
7.1
作者：
Bargar C;Wang W;Gunzler SA;LeFevre A;Wang Z;Lerner AJ;Singh N;Tatsuoka C;Appleby B;Zhu X;Xu R;Haroutunian V;Zou WQ;Ma J;Chen SG
通讯作者：
Chen SG
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.1
作者：
Groveman BR;Orrù CD;Hughson AG;Raymond LD;Zanusso G;Ghetti B;Campbell KJ;Safar J;Galasko D;Caughey B
通讯作者：
Caughey B
DOI：
10.1002/anie.202014898
发表时间：
2021-05-17
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Bhumkar A;Magnan C;Lau D;Jun ESW;Dzamko N;Gambin Y;Sierecki E
通讯作者：
Sierecki E