Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS

Raphaelle Luisier, Giulia E. Tyzack, Claire E. Hall, Jamie S. Mitchell, Helen Devine, Doaa M. Taha, Bilal Malik, Ione Meyer, Linda Greensmith, Jia Newcombe, Jernej Ule, Nicholas M. Luscombe () and Rickie Patani ()
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Raphaelle Luisier: The Francis Crick Institute
Giulia E. Tyzack: The Francis Crick Institute
Claire E. Hall: UCL Institute of Neurology, Queen Square
Jamie S. Mitchell: UCL Institute of Neurology, Queen Square
Helen Devine: UCL Institute of Neurology, Queen Square
Doaa M. Taha: UCL Institute of Neurology, Queen Square
Bilal Malik: UCL Institute of Neurology, Queen Square
Ione Meyer: UCL Institute of Neurology, Queen Square
Linda Greensmith: UCL Institute of Neurology, Queen Square
Jia Newcombe: UCL Institute of Neurology, Queen Square
Jernej Ule: The Francis Crick Institute
Nicholas M. Luscombe: The Francis Crick Institute
Rickie Patani: The Francis Crick Institute

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate ubiquitously expressed regulators of RNA processing. To understand the molecular impact of ALS-causing mutations on neuronal development and disease, we analysed transcriptomes during in vitro differentiation of motor neurons (MNs) from human control and patient-specific VCP mutant induced-pluripotent stem cells (iPSCs). We identify increased intron retention (IR) as a dominant feature of the splicing programme during early neural differentiation. Importantly, IR occurs prematurely in VCP mutant cultures compared with control counterparts. These aberrant IR events are also seen in independent RNAseq data sets from SOD1- and FUS-mutant MNs. The most significant IR is seen in the SFPQ transcript. The SFPQ protein binds extensively to its retained intron, exhibits lower nuclear abundance in VCP mutant cultures and is lost from nuclei of MNs in mouse models and human sporadic ALS. Collectively, we demonstrate SFPQ IR and nuclear loss as molecular hallmarks of familial and sporadic ALS.

Date: 2018
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DOI: 10.1038/s41467-018-04373-8

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