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

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 Bact 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 Bact 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.

Parkinsonism-hyperpyrexia syndrome after withdrawal of antiparkinsonian drugs and deep brain stimulation surgery

Background:Parkinsonism-hyperpyrexia syndrome (PHS) is a rare but potentially fatal condition in patients with Parkinson's disease.Deep brain stimulation (DBS) is a widely used and efficacious treatment for advanced Parkinson's disease.Case presentation:Here,we report a case of PHS in a patient who first underwent withdrawal of antiparkinsonian medications and then bilateral subthalamic nucleus DBS.Conclusions:Patients should be advised to gradually decrease rather than suddenly stop antiparkinsonian medications when they must stop taking a medication and antiparkinsonian medications should be reintroduced as soon as possible after surgery.