GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson's Disease.
GBA Mutations Influence the Release and Pathological Effects of Small Extracellular Vesicles from Fibroblasts of Patients with Parkinson's Disease.
复制标题
DOI：
10.3390/ijms22042215
复制
发表时间：
2021-02-23
影响因子：
5.6
通讯作者：
Blandini F
中科院分区：
文献类型：
--
作者：
Cerri S;Ghezzi C;Ongari G;Croce S;Avenali M;Zangaglia R;Di Monte DA;Valente EM;Blandini F
编码溶酶体糖脑苷酶（GCase）的GBA基因的杂合突变是已知的帕金森病（PD）最强的遗传危险因素。在不同GBA突变携带者中观察到的PD风险增加的分子机制和可变表型尚未完全阐明。细胞外囊泡（EVs）在神经退行性疾病中越来越重要，因为它们可以运载病理分子，潜在地促进疾病的传播。越来越多的证据表明，内体-溶酶体途径的扰动可以影响EV的释放和组成。在这里，我们研究GCase缺乏对EV释放的影响及其在受体细胞中的作用。从PD患者的成纤维细胞系（有或没有GBA突变）上清液中进行超离心纯化，并通过纳米颗粒跟踪分析进行定量。用过表达α-突触核蛋白（α-syn）的SH-SY5Y细胞来评估患者源性小ev影响α-syn表达的能力。我们观察到GCase活性缺陷促进ev的释放，与突变严重程度无关。此外，携带严重突变的PD成纤维细胞释放的小ev增加了细胞内磷酸化α-syn的水平。总之，我们的工作表明，小EV运输的失调和α -突触核蛋白的错误处理可能在gba相关的PD中发挥作用。
Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), are the strongest known genetic risk factor for Parkinson’s disease (PD). The molecular mechanisms underlying the increased PD risk and the variable phenotypes observed in carriers of different GBA mutations are not yet fully elucidated. Extracellular vesicles (EVs) have gained increasing importance in neurodegenerative diseases since they can vehiculate pathological molecules potentially promoting disease propagation. Accumulating evidence showed that perturbations of the endosomal–lysosomal pathway can affect EV release and composition. Here, we investigate the impact of GCase deficiency on EV release and their effect in recipient cells. EVs were purified by ultracentrifugation from the supernatant of fibroblast cell lines derived from PD patients with or without GBA mutations and quantified by nanoparticle tracking analysis. SH-SY5Y cells over-expressing alpha-synuclein (α-syn) were used to assess the ability of patient-derived small EVs to affect α-syn expression. We observed that defective GCase activity promotes the release of EVs, independently of mutation severity. Moreover, small EVs released from PD fibroblasts carrying severe mutations increased the intra-cellular levels of phosphorylated α-syn. In summary, our work shows that the dysregulation of small EV trafficking and alpha-synuclein mishandling may play a role in GBA-associated PD.
登录
查看更多内容
影响因子：
16
作者：
Mateescu B;Kowal EJ;van Balkom BW;Bartel S;Bhattacharyya SN;Buzás EI;Buck AH;de Candia P;Chow FW;Das S;Driedonks TA;Fernández-Messina L;Haderk F;Hill AF;Jones JC;Van Keuren-Jensen KR;Lai CP;Lässer C;Liegro ID;Lunavat TR;Lorenowicz MJ;Maas SL;Mäger I;Mittelbrunn M;Momma S;Mukherjee K;Nawaz M;Pegtel DM;Pfaffl MW;Schiffelers RM;Tahara H;Théry C;Tosar JP;Wauben MH;Witwer KW;Nolte-'t Hoen EN
通讯作者：
Nolte-'t Hoen EN
影响因子：
16
作者：
Lötvall J;Hill AF;Hochberg F;Buzás EI;Di Vizio D;Gardiner C;Gho YS;Kurochkin IV;Mathivanan S;Quesenberry P;Sahoo S;Tahara H;Wauben MH;Witwer KW;Théry C
通讯作者：
Théry C
影响因子：
15.1
作者：
Danzer KM;Kranich LR;Ruf WP;Cagsal-Getkin O;Winslow AR;Zhu L;Vanderburg CR;McLean PJ
通讯作者：
McLean PJ
影响因子：
13.3
作者：
Minakaki, Georgia;Menges, Stefanie;Klucken, Jochen
通讯作者：
Klucken, Jochen
溶酶体状态对细胞外囊泡含量和释放的影响。
影响因子：
13.1
作者：
Eitan, Erez;Suire, Caitlin;Zhang, Shi;Mattson, Mark P.
通讯作者：
Mattson, Mark P.