D Y Mengistu, M Terribili, C Pellacani, L Ciapponi, M Marzullo
{"title":"TDP-43的表观遗传调控:对肌萎缩侧索硬化症的潜在影响。","authors":"D Y Mengistu, M Terribili, C Pellacani, L Ciapponi, M Marzullo","doi":"10.3389/fmmed.2025.1530719","DOIUrl":null,"url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the <i>TARDBP</i> gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating <i>TARDBP</i> expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant <i>TARDBP</i> expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.</p>","PeriodicalId":73090,"journal":{"name":"Frontiers in molecular medicine","volume":"5 ","pages":"1530719"},"PeriodicalIF":0.0000,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865237/pdf/","citationCount":"0","resultStr":"{\"title\":\"Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.\",\"authors\":\"D Y Mengistu, M Terribili, C Pellacani, L Ciapponi, M Marzullo\",\"doi\":\"10.3389/fmmed.2025.1530719\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the <i>TARDBP</i> gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating <i>TARDBP</i> expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant <i>TARDBP</i> expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.</p>\",\"PeriodicalId\":73090,\"journal\":{\"name\":\"Frontiers in molecular medicine\",\"volume\":\"5 \",\"pages\":\"1530719\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-02-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865237/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Frontiers in molecular medicine\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.3389/fmmed.2025.1530719\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in molecular medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.3389/fmmed.2025.1530719","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"","JCRName":"","Score":null,"Total":0}
Epigenetic regulation of TDP-43: potential implications for amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterized by the progressive degeneration of motor neurons. One of the key pathogenic factors implicated in ALS is TDP-43 (TAR DNA-binding protein 43), an RNA-binding protein encoded by the TARDBP gene. Under normal physiological conditions, TDP-43 predominantly resides in the nucleus, where it plays a critical role in regulating gene expression, alternative splicing, RNA transport, and stability. In ALS, TDP-43 undergoes pathological mislocalization from the nucleus to the cytoplasm, disrupting its normal function and contributing to disease progression. The nuclear loss of TDP-43 leads to widespread dysregulation of RNA metabolism. Moreover, mislocalized TDP-43 aggregates in the cytoplasm, acquires toxic properties that sequester essential RNA molecules and proteins. Importantly, deviations in TDP-43 levels, whether excessive or reduced, can lead to cellular dysfunction, and contribute to disease progression, highlighting the delicate balance required for neuronal health. Emerging evidence suggests that epigenetic mechanisms may play a crucial role in regulating TARDBP expression and, consequently, TDP-43 cellular levels. Epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs are increasingly recognized as modulators of gene expression and cellular function in neurodegenerative diseases, including ALS. Dysregulation of these processes could contribute to aberrant TARDBP expression, amplifying TDP-43-associated pathologies. This review explores and summarizes the recent findings on how specific epigenetic modifications influence TDP-43 expression and discusses their possible implications for disease progression.