The interplay between epitranscriptomic RNA modifications and neurodegenerative disorders: Mechanistic insights and potential therapeutic strategies

Ibrain, Год журнала: 2024, Номер 10(4), С. 395 - 426

Опубликована: Ноя. 11, 2024

Abstract Neurodegenerative disorders encompass a group of age‐related conditions characterized by the gradual decline in both structure and functionality central nervous system (CNS). RNA modifications, arising from epitranscriptome or RNA‐modifying protein mutations, have recently been observed to contribute significantly neurodegenerative disorders. Specific modifications like N6‐methyladenine (m6A), N1‐methyladenine (m1A), 5‐methylcytosine (m5C), pseudouridine adenosine‐to‐inosine (A‐to‐I) play key roles, with their regulators serving as crucial therapeutic targets. These epitranscriptomic changes intricately control gene expression, influencing cellular functions contributing disease pathology. Dysregulation metabolism, affecting mRNA processing noncoding biogenesis, is factor these diseases. This review underscores complex relationship between disorders, emphasizing influence modification epitranscriptome, exploring function enzymes processes, investigating functional consequences within pathways, evaluating potential advancements derived assessing epitranscriptome.

Язык: Английский

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Co-Aggregation of TDP-43 with Other Pathogenic Proteins and Their Co-Pathologies in Neurodegenerative Diseases

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(22), С. 12380 - 12380

Опубликована: Ноя. 18, 2024

Pathological aggregation of a specific protein into insoluble aggregates is common hallmark various neurodegenerative diseases (NDDs). In the earlier literature, each NDD characterized by one or two pathogenic proteins, which can serve as disease-specific biomarkers. The these proteins thought to be major cause deleterious result in most NDDs. However, accumulating evidence shows that interact and co-aggregate with other different NDDs, thereby contributing disease onset progression synergistically. During past years, more than type has been found co-exist some individuals, may increase complexity pathogenicity diseases. This article reviews discusses biochemical characteristics molecular mechanisms underlying co-aggregation co-pathologies associated TDP-43 pathology. aggregates, amyotrophic lateral sclerosis (ALS) frontotemporal lobar degeneration (FTLD), often detected such Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) spinocerebellar ataxia 2 (SCA2). many cases, shown multiple vitro vivo. Furthermore, co-occurrence have important consequences aggravate Thus, current viewpoint NDDs their relevance gain insights patho-mechanisms therapeutic potential

Язык: Английский

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m6A RNA modification of mHttintron 1 regulates the generation ofHtt1ain Huntington’s Disease

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Ноя. 10, 2023

ABSTRACT Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expanded, somatically unstable CAG repeat in the first exon of huntingtin gene ( HTT) . In presence expanded repeat, mRNA undergoes aberrant processing that generates HTT1a transcripts with 1 and intron sequences, which encodes aggregation-prone pathogenic HTTexon protein. The regulatory mechanisms contribute to production are not fully understood. previous transcriptome-wide m6A landscape study performed Hdh +/Q111 knock-in mice, we have found proximal region exon1-intron splice site Htt RNA highly modified m6A. Several pieces evidence demonstrated involved splicing. Therefore, this set out explore impact modifications generation Htt1a We show striatum mice enriched intronic sequences 5’ cryptic poly (A) sites (IpA1 IpA2) at 680 1145 bp into as well polyadenylated mRNA. also verified specific m6A-modified near exon1-intron1 donor site. Intronic HTT methylation was recapitulated human samples showing significantly increased ratio HD putamen post-mortem fibroblast cell lines from pre-symptomatic symptomatic patients. order test hypothesis modification mutant processing, pharmacological inhibition METTL3 targeted demethylation cells using dCas13-ALKBH5 system. transcript levels regulated status 1. Site-specific manipulation editing system resulted decreased expression , accompanied reduction DNA damage, major hallmark HD. Finally, propose likely dependent on repeats. These findings provide insight role aberrantly spliced important implications for therapeutic strategies.

Язык: Английский

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