中文摘要：

α- 突觸核蛋白（α-syn）原纖維會在帕金森病患者體內蓄積，并在細胞間傳播，通過模板誘導蛋白錯誤折疊，進而誘發(fā)神經(jīng)退行性病變。α- 突觸核蛋白原纖維進入健康神經(jīng)元是該病理過程的關鍵環(huán)節(jié)。

本研究全面篩選了可與 α- 突觸核蛋白原纖維結合的膜蛋白質組，鑒定出mGluR4與NPDC1兩種黑質表面蛋白，二者能夠結合并介導 α- 突觸核蛋白原纖維的細胞內吞。

向野生型小鼠紋狀體內注射 α- 突觸核蛋白原纖維，會造成黑質多巴胺能神經(jīng)元損傷；而敲除Grm4或Npdc1任一基因，均可對多巴胺能神經(jīng)元起到保護作用。研究發(fā)現(xiàn)，mGluR4 與 NPDC1 可形成復合物，并調控 mGluR4 的生理功能。

同時缺失Grm4和Npdc1的培養(yǎng)神經(jīng)元，無法結合 α- 突觸核蛋白原纖維，也不會出現(xiàn)磷酸化 α- 突觸核蛋白蓄積及突觸丟失現(xiàn)象。Grm4、Npdc1 雙雜合轉基因小鼠的黑質神經(jīng)元可免受 α- 突觸核蛋白原纖維的損傷，證實兩個基因之間存在遺傳互作。

在 α- 突觸核蛋白 A53T 轉基因模型小鼠中，Grm4與Npdc1雙雜合狀態(tài)可顯著延長小鼠生存期、改善運動功能，并維持脊髓運動神經(jīng)元數(shù)量。

綜上，細胞表面 mGluR4–NPDC1 復合物 參與介導了 α- 突觸核蛋白驅動的神經(jīng)退行性病變進程。

英文摘要：

α-Syn fibril entry into healthy neurons is a key step. Here, we comprehensively assessed the membrane proteome for α-syn fibril binding. We identified mGluR4 and NPDC1 as nigral surface proteins binding and internalizing α-syn fibrils. While striatal α-syn fibril injection led to nigral dopamine neuron loss in wild type mice, deletion of either Grm4 or Npdc1 provided protection of dopamine neurons. We observed mGluR4 and Npdc1 to form a complex regulating mGluR4 function. Cultured neurons lacking both Grm4 and Npdc1 fail to bind α-syn fibrils, to accumulate phosphorylated α-syn and to lose synapses. Transheterozygous Grm4, Npdc1 mice showed protection of nigral neurons from α-syn fibrils, demonstrating genetic interaction. For transgenic α-syn A53T mice, double Grm4, Npdc1 heterozygosity increased mouse survival, motor function and spinal motoneuron number. Thus, a cell surface mGluR4–NPDC1 complex participates in α-syn neurodegeneration.

論文信息：

論文題目：mGluR4–NPDC1 complex mediates α-synuclein fibril-induced neurodegeneration

期刊名稱：Nature Communications

時間期卷：17, Article number: 994(2026)

在線時間：2025年12月25日

DOI： doi.org/10.1038/s41467-025-67731-3

產(chǎn)品信息：

貨號：HECA500

規(guī)格：500ml

品牌：Brainbits

產(chǎn)地：美國

名稱：BrainBits 無鈣培養(yǎng)液 E 型

辦事處：靶點科技

Brainbits胚胎型神經(jīng)培養(yǎng)液見刊于Nature Communications：mGluR4–NPDC1 復合物介導 α- 突觸核蛋白原纖維誘導的神經(jīng)退行性病變

Brain bits胚胎E型培養(yǎng)基的材料和方法：

Neuronal culture and PFF exposure

Cortical cells were isolated from the cortices of E16-17 mouse embryos as reported previously49. The embryos were decapitated, and the anterior cortex was dissected out under a stereotactic microscope using BrainBits Hibernate E minus calcium medium, kept on ice. The tissue was then digested with a freshly prepared enzyme solution (Mg/Ca-free HBSS containing 20 U/ml Papain (Worthington LK003178), 3?mM EDTA (AmericanBio), 2?mM CaCl? (VWR E506), and 1?mg/ml DNAse (Sigma DN25)) at 37?°C for 30?min. After digestion, the cell suspension was filtered through a 40?µm cell strainer (Corning, #352340), and the cells were counted and diluted to a concentration of 1 × 10? cells/ml. A 100?µl volume of this suspension was plated onto a PDL-coated 96-well Black/Clear Flat Bottom Plate. The plates were incubated at 37?°C with 5% CO?, and the medium was half-changed every 7 days.

For the binding assay, PFF was added at DIV 17-18 and incubated at 4?°C or 37?°C for 2?h. For the α-syn phosphorylation and synaptic loss assays, PFF were added at DIV 10 and incubated at 37?°C for 7 days.

材料和方法文獻截圖：