Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo.
Progranulin functions as a cathepsin D chaperone to stimulate axonal outgrowth in vivo.
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DOI：
10.1093/hmg/ddx162
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发表时间：
2017-08-01
影响因子：
3.5
通讯作者：
Van Damme P
中科院分区：
文献类型：
--
作者：
Beel S;Moisse M;Damme M;De Muynck L;Robberecht W;Van Den Bosch L;Saftig P;Van Damme P
原颗粒蛋白(GRN)功能突变缺失会导致额颞叶痴呆，但GRN单倍体功能不全如何导致神经元功能障碍仍不清楚。我们之前的研究表明，GRN在体外具有神经营养作用。在这里，我们使用了体内轴突生长系统，并观察到grn−/−小鼠面神经损伤后恢复延迟。这一缺陷通过重新引入人类GRN而得到挽救，并依赖于其C末端和神经元GRN的产生。对损伤后的面部运动核进行的转录组分析表明，组织蛋白酶D(CTSD)是最上调的基因。在衰老的GRN−/−皮层中，CTSD也上调，但相对CTSD活性在外源GRN的作用下降低和提高。此外，GRN及其C端颗粒蛋白结构域颗粒E(GRNE)在体外均能刺激CTSD的蛋白水解性。下拉实验证实了GRN和CTSD之间的直接相互作用。这种与GRNE的相互作用也被观察到，并在不同温度下稳定CTSD酶。研究这种相互作用对体内轴突再生的重要性，我们发现，尽管单独耐受，但GRN和CTSD的联合减少协同减少了轴突生长。我们的数据将GRN和GRNE的神经营养作用与CTSD上的溶酶体伴侣功能联系起来，以维持其蛋白分解能力。
Loss of function mutations in progranulin (GRN) cause frontotemporal dementia, but how GRN haploinsufficiency causes neuronal dysfunction remains unclear. We previously showed that GRN is neurotrophic in vitro. Here, we used an in vivo axonal outgrowth system and observed a delayed recovery in GRN−/− mice after facial nerve injury. This deficit was rescued by reintroduction of human GRN and relied on its C-terminus and on neuronal GRN production. Transcriptome analysis of the facial motor nucleus post injury identified cathepsin D (CTSD) as the most upregulated gene. In aged GRN−/− cortices, CTSD was also upregulated, but the relative CTSD activity was reduced and improved upon exogenous GRN addition. Moreover, GRN and its C-terminal granulin domain granulinE (GrnE) both stimulated the proteolytic activity of CTSD in vitro. Pull-down experiments confirmed a direct interaction between GRN and CTSD. This interaction was also observed with GrnE and stabilized the CTSD enzyme at different temperatures. Investigating the importance of this interaction for axonal regeneration in vivo we found that, although individually tolerated, a combined reduction of GRN and CTSD synergistically reduced axonal outgrowth. Our data links the neurotrophic effect of GRN and GrnE with a lysosomal chaperone function on CTSD to maintain its proteolytic capacity.
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影响因子：
15.1
作者：
Chitramuthu BP;Baranowski DC;Kay DG;Bateman A;Bennett HP
通讯作者：
Bennett HP
影响因子：
64.8
作者：
Cruts, Marc;Gijselinck, Ilse;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
影响因子：
8.8
作者：
Almeida S;Zhang Z;Coppola G;Mao W;Futai K;Karydas A;Geschwind MD;Tartaglia MC;Gao F;Gianni D;Sena-Esteves M;Geschwind DH;Miller BL;Farese RV Jr;Gao FB
通讯作者：
Gao FB
影响因子：
15.9
作者：
Martens, Lauren Henl;Zhang, Jiasheng;Farese, Robert V., Jr.
通讯作者：
Farese, Robert V., Jr.
影响因子：
64.5
作者：
Lui H;Zhang J;Makinson SR;Cahill MK;Kelley KW;Huang HY;Shang Y;Oldham MC;Martens LH;Gao F;Coppola G;Sloan SA;Hsieh CL;Kim CC;Bigio EH;Weintraub S;Mesulam MM;Rademakers R;Mackenzie IR;Seeley WW;Karydas A;Miller BL;Borroni B;Ghidoni R;Farese RV Jr;Paz JT;Barres BA;Huang EJ
通讯作者：
Huang EJ