Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders.
Altered ceramide metabolism is a feature in the extracellular vesicle-mediated spread of alpha-synuclein in Lewy body disorders.
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DOI：
10.1007/s00401-021-02367-3
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发表时间：
2021-12
影响因子：
12.7
通讯作者：
Morris CM
中科院分区：
文献类型：
--
作者：
Kurzawa-Akanbi M;Tammireddy S;Fabrik I;Gliaudelytė L;Doherty MK;Heap R;Matečko-Burmann I;Burmann BM;Trost M;Lucocq JM;Gherman AV;Fairfoul G;Singh P;Burté F;Green A;McKeith IG;Härtlova A;Whitfield PD;Morris CM
葡萄糖脑苷脂酶（GBA）突变是路易体疾病（LBD）最常见的遗传风险因素-统称帕金森病，帕金森病痴呆和路易体痴呆。尽管存在这种遗传关联，但仍不清楚GBA突变如何增加LBD的易感性。我们研究了LBD特异性葡萄糖脑苷脂酶缺陷、GBA相关通路和LBD和对照组（有和无GBA突变）脑组织中α-突触核蛋白水平之间的关系。我们表明，LBD的特点是改变鞘脂代谢与神经酰胺类显着升高，无论GBA突变。由于细胞外囊泡（EV）可以通过传播疾病相关的脂质和蛋白质参与LBD的发病机制，我们调查了来自死后脑脊液（CSF）和GBA突变携带者和非携带者的脑组织的EV。从LBD CSF和额叶皮质纯化的EV大量装载有神经酰胺和神经变性相关蛋白，包括α-突触核蛋白和tau。我们的体外研究表明，LBD EV构成了一个“病理包装”，能够诱导野生型α-突触核蛋白的聚集，通过α-突触核蛋白-神经酰胺相互作用和病理形式的α-突触核蛋白的存在的组合介导。总之，我们的研究结果表明，神经酰胺代谢异常是LBD的一个特征，构成了一个有前途的生物标志物来源，GBA突变可能会加速通过内溶酶体缺陷发生在散发性LBD的病理过程。在线版本包含补充材料，可通过10.1007/s 00401 -021-02367-3获得。
Mutations in glucocerebrosidase (GBA) are the most prevalent genetic risk factor for Lewy body disorders (LBD)—collectively Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies. Despite this genetic association, it remains unclear how GBA mutations increase susceptibility to develop LBD. We investigated relationships between LBD-specific glucocerebrosidase deficits, GBA-related pathways, and α-synuclein levels in brain tissue from LBD and controls, with and without GBA mutations. We show that LBD is characterised by altered sphingolipid metabolism with prominent elevation of ceramide species, regardless of GBA mutations. Since extracellular vesicles (EV) could be involved in LBD pathogenesis by spreading disease-linked lipids and proteins, we investigated EV derived from post-mortem cerebrospinal fluid (CSF) and brain tissue from GBA mutation carriers and non-carriers. EV purified from LBD CSF and frontal cortex were heavily loaded with ceramides and neurodegeneration-linked proteins including alpha-synuclein and tau. Our in vitro studies demonstrate that LBD EV constitute a “pathological package” capable of inducing aggregation of wild-type alpha-synuclein, mediated through a combination of alpha-synuclein–ceramide interaction and the presence of pathological forms of alpha-synuclein. Together, our findings indicate that abnormalities in ceramide metabolism are a feature of LBD, constituting a promising source of biomarkers, and that GBA mutations likely accelerate the pathological process occurring in sporadic LBD through endolysosomal deficiency. The online version contains supplementary material available at 10.1007/s00401-021-02367-3.
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影响因子：
5.6
作者：
Bluhm A;Schrempel S;von Hörsten S;Schulze A;Roßner S
通讯作者：
Roßner S
影响因子：
7.4
作者：
Boutin, Michel;Sun, Ying;Auray-Blais, Christiane
通讯作者：
Auray-Blais, Christiane
影响因子：
2.2
作者：
Bermel, W;Bertini, I;Pierattelli, R
通讯作者：
Pierattelli, R
在GBA-N370S帕金森氏菌IPSC衍生的多巴胺神经元中，ER应力和自噬扰动导致细胞外α-突触核蛋白升高。
影响因子：
5.9
作者：
Fernandes HJ;Hartfield EM;Christian HC;Emmanoulidou E;Zheng Y;Booth H;Bogetofte H;Lang C;Ryan BJ;Sardi SP;Badger J;Vowles J;Evetts S;Tofaris GK;Vekrellis K;Talbot K;Hu MT;James W;Cowley SA;Wade-Martins R
通讯作者：
Wade-Martins R
DOI：
10.1016/j.micron.2017.03.019
发表时间：
2017-08
期刊：
Micron (Oxford, England : 1993)
影响因子：
--
作者：
Asadi J;Ferguson S;Raja H;Hacker C;Marius P;Ward R;Pliotas C;Naismith J;Lucocq J
通讯作者：
Lucocq J