Heterogeneity in α-synuclein fibril activity correlates to disease phenotypes in Lewy body dementia.
Heterogeneity in α-synuclein fibril activity correlates to disease phenotypes in Lewy body dementia.
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DOI：
10.1007/s00401-021-02288-1
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发表时间：
2021-04
影响因子：
12.7
通讯作者：
West AB
中科院分区：
文献类型：
--
作者：
Sokratian A;Ziaee J;Kelly K;Chang A;Bryant N;Wang S;Xu E;Li JY;Wang SH;Ervin J;Swain SM;Liddle RA;West AB
α-突触核蛋白聚集是路易体痴呆病理改变的基础。最近的研究强调了患者群体中与α-突触核蛋白聚集体相关的结构变异。在这里，我们建立了一种定量实时震动诱导转换(qRT-QuIC)方法来测量组织和脑脊液中允许的α-突触核蛋白原纤维模板活性。该分析是通过稳定的超短纤维颗粒的参照板固定的。在人源化α-突触核蛋白转基因小鼠中，qRT-QuIC在易感神经元中磷酸化α-突触核蛋白沉积前几个月确定了大脑中不同水平的纤维活性。路易体痴呆患者大脑皮质提取物中α-突触核蛋白原纤维的活性与匹配的脑室脑脊液中的活性相关。脑脊液中α-突触核蛋白原纤维活性的升高对应于DLB存活率的降低。从具有高纤维活性的病例中扩增的α-突触核蛋白原纤维颗粒在神经元中形成新的包涵体方面优于从具有低纤维活性的病例中扩增出的相同数量的原纤维颗粒。我们的结果强调了一种以前未知的广泛的DLB纤维模板活性的异质性，这可能有助于疾病的表型。我们预测，定量评估脑脊液中与脑组织中的纤维活动相关的纤维活性将有助于对患者群体进行分层，并衡量治疗反应，以促进α-突触核蛋白靶向疗法的发展。
α-Synuclein aggregation underlies pathological changes in Lewy body dementia. Recent studies highlight structural variabilities associated with α-synuclein aggregates in patient populations. Here, we develop a quantitative real-time quaking-induced conversion (qRT-QuIC) assay to measure permissive α-synuclein fibril-templating activity in tissues and cerebrospinal fluid (CSF). The assay is anchored through reference panels of stabilized ultra-short fibril particles. In humanized α-synuclein transgenic mice, qRT-QuIC identifies differential levels of fibril activity across the brain months before the deposition of phosphorylated α-synuclein in susceptible neurons. α-Synuclein fibril activity in cortical brain extracts from dementia with Lewy bodies (DLB) correlates with activity in matched ventricular CSF. Elevated α-synuclein fibril activity in CSF corresponds to reduced survival in DLB. α-Synuclein fibril particles amplified from cases with high fibril activity show superior templating in the formation of new inclusions in neurons relative to the same number of fibril particles amplified from DLB cases with low fibril activity. Our results highlight a previously unknown broad heterogeneity of fibril-templating activities in DLB that may contribute to disease phenotypes. We predict that quantitative assessments of fibril activities in CSF that correlate to fibril activities in brain tissue will help stratify patient populations as well as measure therapeutic responses to facilitate the development of α-synuclein-targeted therapeutics.
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影响因子：
8.6
作者：
Kang, Un Jung;Boehme, Amelia K.;Soto, Claudio
通讯作者：
Soto, Claudio
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：
10.1073/pnas.97.2.571
发表时间：
2000-01-18
影响因子：
11.1
作者：
Conway, KA;Lee, SJ;Lansbury, PT
通讯作者：
Lansbury, PT
DOI：
10.1073/pnas.0901422106
发表时间：
2009-07-07
影响因子：
11.1
作者：
Chatani, Eri;Lee, Young-Ho;Goto, Yuji
通讯作者：
Goto, Yuji
影响因子：
15
作者：
Guerin, Gerald;Wang, Hai;Winnik, Mitchell A.
通讯作者：
Winnik, Mitchell A.