FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice.
FUS/TLS acts as an aggregation-dependent modifier of polyglutamine disease model mice.
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DOI：
10.1038/srep35236
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发表时间：
2016-10-14
影响因子：
4.6
通讯作者：
Nukina N
中科院分区：
文献类型：
--
作者：
Kino Y;Washizu C;Kurosawa M;Yamada M;Doi H;Takumi T;Adachi H;Katsuno M;Sobue G;Hicks GG;Hattori N;Shimogori T;Nukina N
FUS/TLS 是一种 RNA/DNA 结合蛋白，与肌萎缩侧索硬化症和额颞叶变性等神经退行性疾病相关。此前，我们发现 FUS/TLS N 端的类朊病毒结构域介导 FUS/TLS 与亨廷顿舞蹈症 (HD) 基因产物突变型亨廷顿蛋白之间的共聚集。在这里，我们发现 FUS/TLS 的杂合敲除使 HD 模型小鼠的表型恶化，但不是脊髓和延髓性肌萎缩症 (SBMA) 模型小鼠的表型恶化。这种差异与疾病蛋白和 FUS/TLS 之间的病理关联程度相关。FUS/TLS 和突变亨廷顿蛋白之间的共聚集导致 HD 小鼠中游离 FUS/TLS 蛋白的消耗，在 SDS-PAGE 分析中检测为单体。最近，我们发现FUS/TLS 旁系同源物 TAF15 和 EWS 在纯合 FUS/TLS 敲除小鼠中表达上调，这两种蛋白在 HD-TLS+/- 双突变小鼠中表达上调，与 FUS/TLS 的功能损伤一致，这些结果表明 FUS/TLS 的共聚集是 HD 疾病表型的限速因素，并且内含物可能与 FUS/TLS 的功能损伤一致。此外，我们的结果强调了内含物是神经退行性变的潜在调节剂的储存库。
FUS/TLS is an RNA/DNA-binding protein associated with neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Previously, we found that a prion-like domain in the N-terminus of FUS/TLS mediates co-aggregation between FUS/TLS and mutant huntingtin, the gene product of Huntington’s disease (HD). Here, we show that heterozygous knockout of FUS/TLS worsened the phenotypes of model mice of (HD, but not spinal and bulbar muscular atrophy (SBMA). This difference was correlated with the degree of pathological association between disease proteins and FUS/TLS. Co-aggregation between FUS/TLS and mutant huntingtin resulted in the depletion of free FUS/TLS protein in HD mice that was detected as a monomer in SDS-PAGE analysis. Recently, we found that FUS/TLS paralogs, TAF15 and EWS, were up-regulated in homozygous FUS/TLS knockout mice. These two proteins were up-regulated in both HD and FUS/TLS heterozygote mice, and were further elevated in HD-TLS+/− double mutant mice, consistent with the functional impairment of FUS/TLS. These results suggest that FUS/TLS sequestration by co-aggregation is a rate-limiting factor of disease phenotypes of HD and that inclusions may have an adverse aspect, rather than being simply benign or protective. In addition, our results highlight inclusions as repositories of potential modifiers of neurodegeneration.
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DOI：
10.1083/jcb.141.5.1097
发表时间：
1998-06-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hackam AS;Singaraja R;Wellington CL;Metzler M;McCutcheon K;Zhang T;Kalchman M;Hayden MR
通讯作者：
Hayden MR
影响因子：
16.2
作者：
Katsuno, M;Adachi, H;Sobue, G
通讯作者：
Sobue, G
影响因子：
3.5
作者：
Doi, H;Mitsui, K;Nukina, N
通讯作者：
Nukina, N
影响因子：
4.2
作者：
Fratta, Pietro;Malik, Bilal;Greensmith, Linda
通讯作者：
Greensmith, Linda
影响因子：
14.8
作者：
Huang, Da Wei;Sherman, Brad T.;Lempicki, Richard A.
通讯作者：
Lempicki, Richard A.