Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking.
Rescue of α-synuclein aggregation in Parkinson's patient neurons by synergistic enhancement of ER proteostasis and protein trafficking.
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DOI：
10.1016/j.neuron.2021.10.032
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发表时间：
2022-02-02
期刊：
影响因子：
16.2
通讯作者：
Mazzulli JR
中科院分区：
文献类型：
--
作者：
Stojkovska I;Wani WY;Zunke F;Belur NR;Pavlenko EA;Mwenda N;Sharma K;Francelle L;Mazzulli JR
神经退行性疾病的特征是蛋白质稳定性崩溃，表现为脑中不溶蛋白聚集体的积累。蛋白质平衡涉及蛋白质合成、折叠、运输和降解的平衡，但聚集体如何扰乱这些途径尚不清楚。利用帕金森病(PD)患者中脑培养物，我们发现聚集的α-突触核蛋白诱导内质网(ER)碎裂并损害ER蛋白的折叠能力，导致未成熟的溶酶体β-葡萄糖脑苷酶的错误折叠和聚集。尽管如此，PD神经元未能启动未折叠的蛋白质反应，表明内质网中错误折叠的蛋白质信号的感知或转导受到了干扰。小分子增强内质网蛋白抑制机制促进β-葡萄糖脑苷酶的溶解，同时增强转运改善内质网形态、溶酶体功能，降低α-突触核蛋白。我们的研究表明，聚集的α-突触核蛋白扰乱了神经元对内质网错误折叠蛋白的反应能力，多个蛋白平衡分支的协同增强可能为帕金森病提供治疗益处。Stojkovska等人。发现帕金森病患者神经元积累α-突触核蛋白，缺乏识别内质网(ER)错误折叠蛋白的能力，从而导致未成熟溶酶体水解酶的病理性聚集。这一表型可通过联合增强内质网蛋白平衡和蛋白转运，导致溶酶体激活和α-突触核蛋白减少而得到挽救。
Neurodegenerative disorders are characterized by a collapse in proteostasis, shown by the accumulation of insoluble protein aggregates in the brain. Proteostasis involves a balance of protein synthesis, folding, trafficking, and degradation, but how aggregates perturb these pathways is unknown. Using Parkinson’s disease (PD) patient midbrain cultures, we find that aggregated α-synuclein induces endoplasmic reticulum (ER) fragmentation and compromises ER protein folding capacity, leading to misfolding and aggregation of immature lysosomal β-glucocerebrosidase. Despite this, PD neurons fail to initiate the unfolded protein response, indicating perturbations in sensing or transducing protein misfolding signals in the ER. Small molecule enhancement of ER proteostasis machinery promotes β-glucocerebrosidase solubility, while simultaneous enhancement of trafficking improves ER morphology, lysosomal function, and reduces α-synuclein. Our studies suggest that aggregated a-synuclein perturbs the ability of neurons to respond to misfolded proteins in the ER, and that synergistic enhancement of multiple proteostasis branches may provide therapeutic benefit in PD. Stojkovska et al. found that Parkinson’s patient neurons accumulate α-synuclein and are deficient at recognizing misfolded proteins in the endoplasmic reticulum (ER), inducing pathogenic aggregation of immature lysosomal hydrolases. This phenotype is rescued by combined enhancement of ER proteostasis and protein trafficking, leading to lysosomal activation and reduction of a-synuclein.
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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：
14.8
作者：
Grandjean JMD;Madhavan A;Cech L;Seguinot BO;Paxman RJ;Smith E;Scampavia L;Powers ET;Cooley CB;Plate L;Spicer TP;Kelly JW;Wiseman RL
通讯作者：
Wiseman RL
影响因子：
30.8
作者：
Chia R;Sabir MS;Bandres-Ciga S;Saez-Atienzar S;Reynolds RH;Gustavsson E;Walton RL;Ahmed S;Viollet C;Ding J;Makarious MB;Diez-Fairen M;Portley MK;Shah Z;Abramzon Y;Hernandez DG;Blauwendraat C;Stone DJ;Eicher J;Parkkinen L;Ansorge O;Clark L;Honig LS;Marder K;Lemstra A;St George-Hyslop P;Londos E;Morgan K;Lashley T;Warner TT;Jaunmuktane Z;Galasko D;Santana I;Tienari PJ;Myllykangas L;Oinas M;Cairns NJ;Morris JC;Halliday GM;Van Deerlin VM;Trojanowski JQ;Grassano M;Calvo A;Mora G;Canosa A;Floris G;Bohannan RC;Brett F;Gan-Or Z;Geiger JT;Moore A;May P;Krüger R;Goldstein DS;Lopez G;Tayebi N;Sidransky E;American Genome Center;Norcliffe-Kaufmann L;Palma JA;Kaufmann H;Shakkottai VG;Perkins M;Newell KL;Gasser T;Schulte C;Landi F;Salvi E;Cusi D;Masliah E;Kim RC;Caraway CA;Monuki ES;Brunetti M;Dawson TM;Rosenthal LS;Albert MS;Pletnikova O;Troncoso JC;Flanagan ME;Mao Q;Bigio EH;Rodríguez-Rodríguez E;Infante J;Lage C;González-Aramburu I;Sanchez-Juan P;Ghetti B;Keith J;Black SE;Masellis M;Rogaeva E;Duyckaerts C;Brice A;Lesage S;Xiromerisiou G;Barrett MJ;Tilley BS;Gentleman S;Logroscino G;Serrano GE;Beach TG;McKeith IG;Thomas AJ;Attems J;Morris CM;Palmer L;Love S;Troakes C;Al-Sarraj S;Hodges AK;Aarsland D;Klein G;Kaiser SM;Woltjer R;Pastor P;Bekris LM;Leverenz JB;Besser LM;Kuzma A;Renton AE;Goate A;Bennett DA;Scherzer CR;Morris HR;Ferrari R;Albani D;Pickering-Brown S;Faber K;Kukull WA;Morenas-Rodriguez E;Lleó A;Fortea J;Alcolea D;Clarimon J;Nalls MA;Ferrucci L;Resnick SM;Tanaka T;Foroud TM;Graff-Radford NR;Wszolek ZK;Ferman T;Boeve BF;Hardy JA;Topol EJ;Torkamani A;Singleton AB;Ryten M;Dickson DW;Chiò A;Ross OA;Gibbs JR;Dalgard CL;Traynor BJ;Scholz SW
通讯作者：
Scholz SW
影响因子：
3.5
作者：
Heman-Ackah, Sabrina M.;Manzano, Raquel;Wood, Matthew J. A.
通讯作者：
Wood, Matthew J. A.
影响因子：
64.8
作者：
Calfon, M;Zeng, HQ;Ron, D
通讯作者：
Ron, D