Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures.
Neuronal lysosomal dysfunction releases exosomes harboring APP C-terminal fragments and unique lipid signatures.
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神经元溶酶体功能障碍释放出具有应用C末端片段和独特脂质特征的外泌体。
DOI：
10.1038/s41467-017-02533-w
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发表时间：
2018-01-18
影响因子：
16.6
通讯作者：
Di Paolo G
中科院分区：
文献类型：
--
作者：
Miranda AM;Lasiecka ZM;Xu Y;Neufeld J;Shahriar S;Simoes S;Chan RB;Oliveira TG;Small SA;Di Paolo G
内溶酶体和自噬功能缺陷越来越多地被视为神经退行性疾病的关键病理特征。这些功能的主要调节者是磷脂酰肌醇-3-磷酸(PI3P)，这是一种主要由III类PI 3-激酶Vps34合成的磷脂。在此，我们报道了在体外和体内，神经元Vps34功能的破坏会损害自噬、溶酶体的降解以及脂类代谢，从而导致内膜的损伤。PI3P缺乏也促进了独特的外体的分泌，这些外体富含未消化的溶酶体底物，包括淀粉样前体蛋白C末端片段(APP-CTF)、特定的鞘磷脂和磷脂双(单酰甘油)磷酸(BMP)，它通常存在于内溶酶体的内部小泡中。这些外切体的分泌需要中性鞘磷脂酶2和鞘磷脂的合成。我们的结果揭示了一种动态平衡反应，通过分泌非典型外切体消除溶酶体废物来对抗溶酶体功能障碍，并将外切体APP-CTF和BMP确定为与神经退行性疾病相关的内溶酶体功能障碍的候选生物标志物。神经退行性变越来越多地与内溶酶体和自噬功能障碍有关。在这里，Miranda和他的同事们展示了神经元PI3P/Vps34信号的中断导致内溶体膜损伤和APP-CTF和BMP阳性外体中未消化物质的异常释放。
Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders. Neurodegeneration is increasingly associated with endolysosomal and autophagy dysfunction. Here, Miranda and colleagues show that disruption of neuronal PI3P/Vps34 signaling leads to endolysosomal membrane damage and aberrant release of undigested material in APP-CTF- and BMP-positive exosomes.
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影响因子：
15.1
作者：
Guix FX;Sannerud R;Berditchevski F;Arranz AM;Horré K;Snellinx A;Thathiah A;Saido T;Saito T;Rajesh S;Overduin M;Kumar-Singh S;Radaelli E;Corthout N;Colombelli J;Tosi S;Munck S;Salas IH;Annaert W;De Strooper B
通讯作者：
De Strooper B
影响因子：
3.7
作者：
Freeman D;Cedillos R;Choyke S;Lukic Z;McGuire K;Marvin S;Burrage AM;Sudholt S;Rana A;O'Connor C;Wiethoff CM;Campbell EM
通讯作者：
Campbell EM
影响因子：
4.8
作者：
Chan, Robin B.;Oliveira, Tiago G.;Di Paolo, Gilbert
通讯作者：
Di Paolo, Gilbert
DOI：
10.1073/pnas.0908953107
发表时间：
2010-01-26
影响因子：
11.1
作者：
Jiang, Ying;Mullaney, Kerry A.;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
12.4
作者：
Gabande-Rodriguez, E.;Boya, P.;Ledesma, M. D.
通讯作者：
Ledesma, M. D.