{"title":"Molecular mechanisms linking loss of TDP-43 function to amyotrophic lateral sclerosis/frontotemporal dementia-related genes","authors":"","doi":"10.1016/j.neures.2024.05.001","DOIUrl":null,"url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion and cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43). TDP-43 plays a key role in regulating the splicing of numerous genes, including <em>TARDBP</em>. This review aims to delineate two aspects of ALS/FTD pathogenesis associated with TDP-43 function. First, we described novel mechanistic insights into the splicing of <em>UNC13A</em>, a TDP-43 target gene. Single nucleotide polymorphisms (SNPs) in <em>UNC13A</em> are the most common risk factors for ALS/FTD. We found that TDP-43 represses “cryptic exon” inclusion during <em>UNC13A</em> RNA splicing. A risk-associated SNP in this exon results in increased RNA levels of <em>UNC13A</em> retaining the cryptic exon. Second, we described the perturbation of the TDP-43 autoregulatory mechanism caused by age-related DNA demethylation. Aging is a major risk factor for sporadic ALS/FTD. Typically, TDP-43 levels are regulated via alternative splicing of <em>TARDBP</em> mRNA. This review focused on that <em>TARDBP</em> methylation is altered by aging, thereby disrupting TDP-43 autoregulation. It was found that demethylation reduces the efficiency of alternative splicing and increases <em>TARDBP</em> mRNA levels. Moreover, we demonstrated that, with aging, this region is demethylated in the human motor cortex and is associated with the early onset of ALS.</div></div>","PeriodicalId":19146,"journal":{"name":"Neuroscience Research","volume":"208 ","pages":"Pages 1-7"},"PeriodicalIF":2.4000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neuroscience Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0168010224000634","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are characterized by nuclear depletion and cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43). TDP-43 plays a key role in regulating the splicing of numerous genes, including TARDBP. This review aims to delineate two aspects of ALS/FTD pathogenesis associated with TDP-43 function. First, we described novel mechanistic insights into the splicing of UNC13A, a TDP-43 target gene. Single nucleotide polymorphisms (SNPs) in UNC13A are the most common risk factors for ALS/FTD. We found that TDP-43 represses “cryptic exon” inclusion during UNC13A RNA splicing. A risk-associated SNP in this exon results in increased RNA levels of UNC13A retaining the cryptic exon. Second, we described the perturbation of the TDP-43 autoregulatory mechanism caused by age-related DNA demethylation. Aging is a major risk factor for sporadic ALS/FTD. Typically, TDP-43 levels are regulated via alternative splicing of TARDBP mRNA. This review focused on that TARDBP methylation is altered by aging, thereby disrupting TDP-43 autoregulation. It was found that demethylation reduces the efficiency of alternative splicing and increases TARDBP mRNA levels. Moreover, we demonstrated that, with aging, this region is demethylated in the human motor cortex and is associated with the early onset of ALS.
期刊介绍:
The international journal publishing original full-length research articles, short communications, technical notes, and reviews on all aspects of neuroscience
Neuroscience Research is an international journal for high quality articles in all branches of neuroscience, from the molecular to the behavioral levels. The journal is published in collaboration with the Japan Neuroscience Society and is open to all contributors in the world.