A molecular brake that modulates spliceosome pausing at detained introns contributes to neurodegeneration

Abstract

Emerging evidence suggests that intron-detaining transcripts (IDTs) are a nucleus-detained and polyadenylated mRNA pool for cell to quickly and effectively respond to environmental stimuli and stress. However, the underlying mechanisms of detained intron (DI) splicing are still largely unknown. Here, we suggest that post-transcriptional DI splicing is paused at the B act state, an active spliceosome but not catalytically primed, which depends on Smad Nuclear Interacting Protein 1 (SNIP1) and RNPS1 (a serine-rich RNA binding protein) interaction. RNPS1 and B act components preferentially dock at DIs and the RNPS1 docking is sufficient to trigger spliceosome pausing. Haploinsufficiency of Snip1 attenuates neurodegeneration and globally rescues IDT accumulation caused by a previously reported mutant U2 snRNA, a basal spliceosomal component. Snip1 conditional knockout in the cerebellum decreases DI splicing efficiency and causes neurodegeneration. Therefore, we suggest that SNIP1 and RNPS1 form a molecular brake to promote spliceosome pausing, and that its misregulation contributes to neurodegeneration.

The clinical utilization of SNIP1 and its pathophysiological mechanisms in disease

“…Dysplasia and caspase 9-dependent apoptosis were significantly upregulated in the brain lacking SNIP1. SNIP1 exerts mechanistic control over target genes that promote cell viability and neurogenesis [ 42 ]. The functionality of SNIP1 is influenced by the TGFβ and NF-κB signaling pathways.…”

“…Scholars have observed that SNIP1 facilitates neurogenesis and inhibits cell death in the murine brain development model. Further investigations have also implicated SNIP1 in the prevention of cell death [ 42 , 43 ]. Moreover, the presence of SNIP1 has been found to enhance the interaction between the Polycomb complex PRC2 and the genome, leading to the removal of H3K27me3 from specific target genes [ 44 ].…”

“…Both SNIP1 and PRC2 collaboratively occupy chromatin targets to regulate genetic programming in the brain. The interaction between PRC2 and SNIP1 plays a crucial role in regulating various cellular processes, including cell cycle progression, programmed cell death, and brain development [ 45 ]. However, the specific mechanism by which SNIP1-PRC2 modulates chromatin and coordinates caspase 9-mediated cell death remains incompletely understood, highlighting the need for further investigation.…”

“…Additionally, mutations in SNIP1 have been associated with neurodevelopmental and psychiatric disorders. Specifically, psychomotor delay, epilepsy, and craniofacial malformations have been associated with the SNIP1 variant E366G [ 45 ]. Furthermore, an examination was conducted on publicly available data from the Human Gene Mutation Database and Mastermind, revealing a significant association between epilepsy and cranial dysplasia with a specific SNIP1 variant, namely R111C [ 46 ].…”