Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog.
Cell-type specific differences in promoter activity of the ALS-linked C9orf72 mouse ortholog.
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DOI：
10.1038/s41598-017-05864-2
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发表时间：
2017-07-18
影响因子：
4.6
通讯作者：
Brown SP
中科院分区：
文献类型：
--
作者：
Langseth AJ;Kim J;Ugolino JE;Shah Y;Hwang HY;Wang J;Bergles DE;Brown SP
C9orf72基因中的六核苷酸重复扩增是遗传性神经退行性疾病肌萎缩侧索硬化症(ALS)的最常见原因。功能丧失和功能获得的机制都被认为是这种疾病的基础，但其致病途径还不完全清楚。为了更好地了解不同细胞类型在ALS发病机制中的作用，我们系统地分析了C9orf72小鼠同源基因启动子活性在中枢神经系统中的分布。我们证明C9orf72启动子活性广泛存在于兴奋性和抑制性神经元以及少突胶质细胞和少突胶质前体细胞中。相反，很少有小胶质细胞和星形胶质细胞表现出可检测到的C9orf72启动子活性。虽然在总体水平上，C9orf72启动子活性的分布在很大程度上取决于总体细胞密度，但我们发现，它选择性地富含在ALS中退化的神经元和神经胶质细胞亚群中。具体地说，我们发现C9orf72启动子活性在皮质脊髓和脊髓运动神经元以及受ALS影响的脑区的少突胶质细胞中丰富。这些结果表明，神经元和胶质细胞的细胞自主性变化可能有助于C9orf72介导的疾病，就像超氧化物歧化酶-1(SOD1)的突变所显示的那样。
A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited forms of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Both loss-of-function and gain-of-function mechanisms have been proposed to underlie this disease, but the pathogenic pathways are not fully understood. To better understand the involvement of different cell types in the pathogenesis of ALS, we systematically analyzed the distribution of promoter activity of the mouse ortholog of C9orf72 in the central nervous system. We demonstrate that C9orf72 promoter activity is widespread in both excitatory and inhibitory neurons as well as in oligodendrocytes and oligodendrocyte precursor cells. In contrast, few microglia and astrocytes exhibit detectable C9orf72 promoter activity. Although at a gross level, the distribution of C9orf72 promoter activity largely follows overall cellular density, we found that it is selectively enriched in subsets of neurons and glial cells that degenerate in ALS. Specifically, we show that C9orf72 promoter activity is enriched in corticospinal and spinal motor neurons as well as in oligodendrocytes in brain regions that are affected in ALS. These results suggest that cell autonomous changes in both neurons and glia may contribute to C9orf72-mediated disease, as has been shown for mutations in superoxide dismutase-1 (SOD1).
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影响因子：
16.2
作者：
Kang, Shin H.;Fukaya, Masahiro;Yang, Jason K.;Rothstein, Jeffrey D.;Bergles, Dwight E.
通讯作者：
Bergles, Dwight E.
影响因子：
17.1
作者：
Burberry A;Suzuki N;Wang JY;Moccia R;Mordes DA;Stewart MH;Suzuki-Uematsu S;Ghosh S;Singh A;Merkle FT;Koszka K;Li QZ;Zon L;Rossi DJ;Trowbridge JJ;Notarangelo LD;Eggan K
通讯作者：
Eggan K
影响因子：
4.2
作者：
Kohli MA;John-Williams K;Rajbhandary R;Naj A;Whitehead P;Hamilton K;Carney RM;Wright C;Crocco E;Gwirtzman HE;Lang R;Beecham G;Martin ER;Gilbert J;Benatar M;Small GW;Mash D;Byrd G;Haines JL;Pericak-Vance MA;Züchner S
通讯作者：
Züchner S
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
影响因子：
29
作者：
Devenney, Emma;Hornberger, Michael;Hodges, John R.
通讯作者：
Hodges, John R.