Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice.
Progranulin reduces insoluble TDP-43 levels, slows down axonal degeneration and prolongs survival in mutant TDP-43 mice.
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DOI：
10.1186/s13024-018-0288-y
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发表时间：
2018-10-16
影响因子：
15.1
通讯作者：
Van Damme P
中科院分区：
文献类型：
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作者：
Beel S;Herdewyn S;Fazal R;De Decker M;Moisse M;Robberecht W;Van Den Bosch L;Van Damme P
TAR DNA结合蛋白43（TDP-43）是大多数肌萎缩侧索硬化（ALS）患者和约50%的额颞叶痴呆（FTD）患者的主要疾病蛋白。TDP-43病理学不限于编码TDP-43的基因TARDBP中存在错义突变的患者，也发生在没有已知遗传原因的ALS/FTD患者或存在各种其他ALS/FTD基因突变的患者中。导致颗粒蛋白前体蛋白（PGRN）水平降低约50%的颗粒蛋白前体（GRN）突变导致FTD伴TDP-43病理。PGRN的丢失如何导致TDP-43病理学以及PGRN表达是否保护免于TDP-43诱导的神经变性尚不清楚。我们研究了PGRN对TDP-43（A315 T）小鼠神经退行性表型的影响。PGRN降低了不溶性TDP-43的水平，并且脊髓的组织学显示PGRN对侧角中的大轴突纤维的损失具有保护作用，侧角是该小鼠模型中受影响最严重的纤维池。PGRN的过表达显著减缓了疾病进展，延长了中位生存期约130天。转录组分析没有指向受PGRN影响的单一途径，而是指向对不同途径的多效性效应。我们的研究结果揭示了PGRN在减弱突变TDP-43诱导的神经变性中的重要作用。本文的在线版本（10.1186/s13024-018-0288-y）包含补充材料，可供授权用户使用。
TAR DNA binding protein 43 (TDP-43) is the main disease protein in most patients with amyotrophic lateral sclerosis (ALS) and about 50% of patients with frontotemporal dementia (FTD). TDP-43 pathology is not restricted to patients with missense mutations in TARDBP, the gene encoding TDP-43, but also occurs in ALS/FTD patients without known genetic cause or in patients with various other ALS/FTD gene mutations. Mutations in progranulin (GRN), which result in a reduction of ~ 50% of progranulin protein (PGRN) levels, cause FTD with TDP-43 pathology. How loss of PGRN leads to TDP-43 pathology and whether or not PGRN expression protects against TDP-43-induced neurodegeneration is not yet clear. We studied the effect of PGRN on the neurodegenerative phenotype in TDP-43(A315T) mice. PGRN reduced the levels of insoluble TDP-43 and histology of the spinal cord revealed a protective effect of PGRN on the loss of large axon fibers in the lateral horn, the most severely affected fiber pool in this mouse model. Overexpression of PGRN significantly slowed down disease progression, extending the median survival by approximately 130 days. A transcriptome analysis did not point towards a single pathway affected by PGRN, but rather towards a pleiotropic effect on different pathways. Our findings reveal an important role of PGRN in attenuating mutant TDP-43-induced neurodegeneration. The online version of this article (10.1186/s13024-018-0288-y) contains supplementary material, which is available to authorized users.
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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：
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
影响因子：
3.5
作者：
Beel S;Moisse M;Damme M;De Muynck L;Robberecht W;Van Den Bosch L;Saftig P;Van Damme P
通讯作者：
Van Damme P
影响因子：
82.9
作者：
通讯作者：
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