中文摘要：

α- 突觸核蛋白（α-syn）原纖維會(huì)在帕金森病患者體內(nèi)蓄積，并在細(xì)胞間傳播，通過(guò)模板誘導(dǎo)蛋白錯(cuò)誤折疊，進(jìn)而誘發(fā)神經(jīng)退行性病變。α- 突觸核蛋白原纖維進(jìn)入健康神經(jīng)元是該病理過(guò)程的關(guān)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(jié)合的膜蛋白質(zhì)組，鑒定出mGluR4與NPDC1兩種黑質(zhì)表面蛋白，二者能夠結(jié)合并介導(dǎo) α- 突觸核蛋白原纖維的細(xì)胞內(nèi)吞。

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

同時(shí)缺失Grm4和Npdc1的培養(yǎng)神經(jīng)元，無(wú)法結(jié)合 α- 突觸核蛋白原纖維，也不會(huì)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(zhuǎn)基因小鼠的黑質(zhì)神經(jīng)元可免受 α- 突觸核蛋白原纖維的損傷，證實(shí)兩個(gè)基因之間存在遺傳互作。

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

綜上，細(xì)胞表面 mGluR4–NPDC1 復(fù)合物 參與介導(dǎo)了 α- 突觸核蛋白驅(qū)動(dòng)的神經(jīng)退行性病變進(jìn)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(shí)間期卷：17, Article number: 994(2026)

在線時(shí)間：2025年12月25日

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

產(chǎn)品信息：

貨號(hào)：HECA500

規(guī)格：500ml

品牌：Brainbits

產(chǎn)地：美國(guó)

名稱：BrainBits 無(wú)鈣培養(yǎng)液 E 型

辦事處：靶點(diǎn)科技

Brainbits胚胎型神經(jīng)培養(yǎng)液見(jiàn)刊于Nature Communications：mGluR4–NPDC1 復(fù)合物介導(dǎo) α- 突觸核蛋白原纖維誘導(dǎo)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(xiàn)截圖：