Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.
Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss.
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DOI：
10.1007/s00401-017-1711-0
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发表时间：
2017-08
影响因子：
12.7
通讯作者：
Edbauer D
中科院分区：
文献类型：
--
作者：
Schludi MH;Becker L;Garrett L;Gendron TF;Zhou Q;Schreiber F;Popper B;Dimou L;Strom TM;Winkelmann J;von Thaden A;Rentzsch K;May S;Michaelsen M;Schwenk BM;Tan J;Schoser B;Dieterich M;Petrucelli L;Hölter SM;Wurst W;Fuchs H;Gailus-Durner V;de Angelis MH;Klopstock T;Arzberger T;Edbauer D
在患有肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的C9 orf 72患者中扩展的（gggcc）n重复的翻译导致丰富的聚-GA夹杂物。为了阐明它们在发病机制中的作用，我们产生了表达密码子修饰的（GA）149与青色荧光蛋白（CFP）缀合的转基因小鼠。转基因小鼠逐步发展聚-GA夹杂物主要在运动神经元和脊髓和脑干的中间神经元和小脑深部核。在小鼠和患者样品中，Poly-GA与p62、Rad 23 b和新鉴定的Mlf 2共聚集。与表达模式一致，4个月大的转基因小鼠表现出异常步态和进行性平衡障碍，但表现出正常的海马依赖性学习和记忆。除了小胶质细胞活化，我们检测到磷酸化的TDP-43，但没有神经元的损失。因此，聚-GA通过炎症和蛋白质螯合触发行为缺陷，这可能有助于C9 orf 72患者的前驱症状和疾病进展。本文的在线版本（doi：10.1007/s 00401 -017-1711-0）包含补充材料，可供授权用户使用。
Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients. The online version of this article (doi:10.1007/s00401-017-1711-0) contains supplementary material, which is available to authorized users.
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DOI：
10.1016/s1474-4422(14)70324-2
发表时间：
2015-03
期刊：
The Lancet. Neurology
影响因子：
--
作者：
Rohrer JD;Nicholas JM;Cash DM;van Swieten J;Dopper E;Jiskoot L;van Minkelen R;Rombouts SA;Cardoso MJ;Clegg S;Espak M;Mead S;Thomas DL;De Vita E;Masellis M;Black SE;Freedman M;Keren R;MacIntosh BJ;Rogaeva E;Tang-Wai D;Tartaglia MC;Laforce R Jr;Tagliavini F;Tiraboschi P;Redaelli V;Prioni S;Grisoli M;Borroni B;Padovani A;Galimberti D;Scarpini E;Arighi A;Fumagalli G;Rowe JB;Coyle-Gilchrist I;Graff C;Fallström M;Jelic V;Ståhlbom AK;Andersson C;Thonberg H;Lilius L;Frisoni GB;Pievani M;Bocchetta M;Benussi L;Ghidoni R;Finger E;Sorbi S;Nacmias B;Lombardi G;Polito C;Warren JD;Ourselin S;Fox NC;Rossor MN;Binetti G
通讯作者：
Binetti G
影响因子：
16.2
作者：
Ash PE;Bieniek KF;Gendron TF;Caulfield T;Lin WL;Dejesus-Hernandez M;van Blitterswijk MM;Jansen-West K;Paul JW 3rd;Rademakers R;Boylan KB;Dickson DW;Petrucelli L
通讯作者：
Petrucelli L
DOI：
10.1126/science.aaf1064
发表时间：
2016-03-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
O'Rourke JG;Bogdanik L;Yáñez A;Lall D;Wolf AJ;Muhammad AK;Ho R;Carmona S;Vit JP;Zarrow J;Kim KJ;Bell S;Harms MB;Miller TM;Dangler CA;Underhill DM;Goodridge HS;Lutz CM;Baloh RH
通讯作者：
Baloh RH
DOI：
10.1037/h0077579
发表时间：
1979-01-01
期刊：
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
影响因子：
--
作者：
BARNES, CA
通讯作者：
BARNES, CA
影响因子：
12.7
作者：
Mackenzie, Ian R.;Arzberger, Thomas;Neumann, Manuela
通讯作者：
Neumann, Manuela