TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.
TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.
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DOI：
10.1371/journal.pbio.3002028
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发表时间：
2023-03
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
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TAR DNA结合蛋白-43（TDP-43）的主要功能是在RNA剪接过程中抑制隐藏外显子的包含。其中一个隐藏的外显子位于UNC 13 A中，UNC 13 A是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）的遗传风险因素。隐藏UNC 13 A在疾病中的积累通过位于隐藏外显子本身内的风险单倍型的存在而提高。在这里，我们揭示了TDP-43末端N-末端对于抑制UNC 13 A隐蔽外显子包含是重要的。此外，我们发现hnRNP L、hnRNP A1和hnRNP A2 B1结合UNC 13 A RNA并抑制隐蔽外显子包含，独立于TDP-43。最后，较高水平的hnRNP L蛋白与ALS/FTD脑中较低的UNC 13 A隐蔽RNA负荷相关。我们的研究结果表明，虽然TDP-43是UNC 13 A隐藏外显子包含的主要阻遏物，但其他hnRNP有助于其调节，并可能作为疾病修饰剂发挥作用。这项研究表明，TDP-43是UNC 13 A中隐藏外显子剪接的最重要阻遏物，UNC 13 A是肌萎缩侧索硬化和额颞叶痴呆的危险因素。虽然TDP-43是UNC 13 A隐藏外显子包含的主要阻遏物，但其他hnRNP有助于其调节，并可能作为疾病调节剂。
A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers. This study shows that TDP-43 is the most important repressor of cryptic exon splicing in UNC13A, a risk factor for amyotrophic lateral sclerosis and frontotemporal dementia. While TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially act as disease modifiers.
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