Cytoplasmic aggregation of mutant FUS causes multistep RNA splicing perturbations in the course of motor neuron pathology.

Autor:	Rezvykh AP; Engelhardt Institute of Molecular Biology of Russian Academy of Sciences, Moscow, 119991, Russian Federation., Ustyugov AA; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry of Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation., Chaprov KD; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry of Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation., Teterina EV; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry of Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation., Nebogatikov VO; Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry of Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation., Spasskaya DS; Engelhardt Institute of Molecular Biology of Russian Academy of Sciences, Moscow, 119991, Russian Federation., Evgen'ev MB; Engelhardt Institute of Molecular Biology of Russian Academy of Sciences, Moscow, 119991, Russian Federation., Morozov AV; Engelhardt Institute of Molecular Biology of Russian Academy of Sciences, Moscow, 119991, Russian Federation., Funikov SY; Engelhardt Institute of Molecular Biology of Russian Academy of Sciences, Moscow, 119991, Russian Federation.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2023 Jun 23; Vol. 51 (11), pp. 5810-5830.
DOI:	10.1093/nar/gkad319
Abstrakt:	Dysfunction of the RNA-binding protein (RBP) FUS implicated in RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and other neurodegenerative diseases. Mutations affecting FUS nuclear localization can drive RNA splicing defects and stimulate the formation of non-amyloid inclusions in affected neurons. However, the mechanism by which FUS mutations contribute to the development of ALS remains uncertain. Here we describe a pattern of RNA splicing changes in the dynamics of the continuous proteinopathy induced by mislocalized FUS. We show that the decrease in intron retention of FUS-associated transcripts represents the hallmark of the pathogenesis of ALS and is the earliest molecular event in the course of progression of the disease. As FUS aggregation increases, the pattern of RNA splicing changes, becoming more complex, including a decrease in the inclusion of neuron-specific microexons and induction of cryptic exon splicing due to the sequestration of additional RBPs into FUS aggregates. Crucially, the identified features of the pathological splicing pattern are also observed in ALS patients in both sporadic and familial cases. Our data provide evidence that both a loss of nuclear FUS function due to mislocalization and the subsequent cytoplasmic aggregation of mutant protein lead to the disruption of RNA splicing in a multistep fashion during FUS aggregation. (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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