Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.
Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies.
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DOI：
10.1016/j.cell.2011.06.001
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发表时间：
2011-07-08
期刊：
影响因子：
64.5
通讯作者：
Krainc D
中科院分区：
文献类型：
--
作者：
Mazzulli JR;Xu YH;Sun Y;Knight AL;McLean PJ;Caldwell GA;Sidransky E;Grabowski GA;Krainc D
帕金森病(PD)是一种成人神经退行性疾病，临床上与溶酶体储存障碍高谢病(GD)有关，但其机制尚不清楚。在这里，我们证明了原代培养或人iPS神经元中GD连接的葡萄糖脑苷酶(GCase)功能的丧失会损害溶酶体蛋白的降解，导致α-突触核蛋白(a-Synuclein，a-syn)的积累，并通过聚集依赖机制导致神经毒性。GCase底物GlcCer通过稳定可溶性低聚中间产物直接影响纯化的a-syn的淀粉样蛋白的形成。我们进一步证明，a-syn抑制神经元和特发性帕金森病脑内正常GCase的溶酶体活性，提示GCase缺失参与了散发性突触核病症的发病机制。这些发现表明，a-syn和GCase的双向效应形成了一个正反馈环，可能导致一种自我传播的疾病。因此，改善GCase对溶酶体的靶向性可能是治疗帕金森病和其他突触核病的一种特异性治疗方法。
Parkinson’s disease (PD), an adult neurodegenerative disorder, has been clinically linked to lysosomal storage disorder, Gaucher disease (GD), but the mechanistic connection has been unknown. Here, we show that functional loss of GD-linked glucocerebrosidase (GCase) in primary cultures or human iPS neurons compromises lysosomal protein degradation, causes accumulation of a-synuclein (a-syn), and results in neurotoxicity through aggregation dependent mechanisms. GlcCer, the GCase substrate, directly influenced amyloid formation of purified a-syn by stabilizing soluble oligomeric intermediates. We further demonstrate that a-syn inhibits the lysosomal activity of normal GCase in neurons and idiopathic PD brain, suggesting that GCase depletion contributes to the pathogenesis of sporadic synucleinopathies. These findings suggest that the bidirectional effect of a-syn and GCase forms a positive feedback loop that may lead to a self-propagating disease. Therefore, improved targeting of GCase to lysosomes may represent a specific therapeutic approach for PD and other synucleinopathies.
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影响因子：
82.9
作者：
Conway, KA;Harper, JD;Lansbury, PT
通讯作者：
Lansbury, PT
影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY
DOI：
10.1073/pnas.61.2.484
发表时间：
1968-01-01
影响因子：
11.1
作者：
LEE, RE
通讯作者：
LEE, RE
DOI：
10.1056/nejmoa0901281
发表时间：
2009-10-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Sidransky E;Nalls MA;Aasly JO;Aharon-Peretz J;Annesi G;Barbosa ER;Bar-Shira A;Berg D;Bras J;Brice A;Chen CM;Clark LN;Condroyer C;De Marco EV;Dürr A;Eblan MJ;Fahn S;Farrer MJ;Fung HC;Gan-Or Z;Gasser T;Gershoni-Baruch R;Giladi N;Griffith A;Gurevich T;Januario C;Kropp P;Lang AE;Lee-Chen GJ;Lesage S;Marder K;Mata IF;Mirelman A;Mitsui J;Mizuta I;Nicoletti G;Oliveira C;Ottman R;Orr-Urtreger A;Pereira LV;Quattrone A;Rogaeva E;Rolfs A;Rosenbaum H;Rozenberg R;Samii A;Samaddar T;Schulte C;Sharma M;Singleton A;Spitz M;Tan EK;Tayebi N;Toda T;Troiano AR;Tsuji S;Wittstock M;Wolfsberg TG;Wu YR;Zabetian CP;Zhao Y;Ziegler SG
通讯作者：
Ziegler SG
影响因子：
2.9
作者：
Martinez, Zak;Zhu, Min;Fink, Anthony L.
通讯作者：
Fink, Anthony L.