fig4

Circadian rhythm in neurodegenerative disease: the role of RNA modifications and potential application of RNA-based therapeutics

Figure 4. Overview of AS and RNA editing. (A) In pre-mRNA splicing, boundaries between intron and exon are recognized as the splice sites, and two consecutive transesterification reactions occur. Internal introns are eliminated from precursor mRNA transcripts through a two-step splicing process. The spliceosome, consisting of 5 snRNP complexes and over 150 accessory proteins, serves to recognize, juxtapose, and facilitate intron excision. As depicted in this figure, ATP-consuming RNA helicases (in humans), namely DDX46, DDX39B, DDX23, SNRNP200, EFTUD2, DHX16, DHX38, DHX8, and DHX15, orchestrate the dynamic process of spliceosome assembly and facilitate the exchanges of snRNPs and other factors. These helicases navigate through kinetic barriers to drive spliceosome activation, catalysis, and product release; (B) A-to-I RNA editing, illustrated on the left, plays a role in neurodegenerative diseases like ALS, AD, and PD, while the right side focuses on m6A RNA methylation and its impact on these conditions. A-to-I RNA editing is a post-transcriptional process that alters dsRNA structures through the deamination of specific adenosines (A) to inosines (I) by the ADAR enzyme family. This modification has an impact on both coding and non-coding transcripts. The schematic diagram represents the m6A RNA modification process and its involvement in neurodegenerative disorders like AD, PD, and ALS. The methylation of RNA m6A is carried out by the methyltransferase complex (writers), including the core subunit heterodimer METTL3/METTL14, along with cofactors like WTAP. Furthermore, erasers such as FTO and ALKBH5 can reversibly remove m6A RNA modifications. Specific readers like YTHDF1-3 recognize and bind to m6A-modified RNAs, influencing RNA processing, transportation, translation, and stability. AS: Alternative splicing; A-to-I: adenosine to inosine; ALS: amyotrophic lateral sclerosis; AD: Alzheimer’s disease; PD: Parkinson’s disease; m6A: N6-methyladenosine; dsRNA: double-stranded RNA; ADAR: adenosine deaminase; WTAP: WT1-associated protein; FTO: alpha-ketoglutarate dependent dioxygenase; ALKBH5: alkB homolog 5.

Ageing and Neurodegenerative Diseases
ISSN 2769-5301 (Online)

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