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bioRxiv · 10.1101/2022.07.18.500445

Deletion induced splicing in RIC3 drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes

BK, T.·Yadav, N.
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Abstract

Nicotinic acetylcholine receptor (nAChR) dysregulation in astrocytes is reported in neurodegenerative disorders. Modulation of nAChRs through agonists confers protection to astrocytes from stress but regulation of chaperones is unclear. Resistance to inhibitors of cholinesterase 3 (RIC3) is a potential chaperone of nAChRs but poorly studied in humans. We characterized RIC3 in astrocytes derived from an isogenic wild-type and a Cas9 edited del human iPSC line harboring a 25bp homozygous deletion in exon2. Altered RIC3 transcript ratio due to deletion induced splicing and an unexpected gain of 7nAChR expression were observed in del astrocytes. Transcriptome analysis showed higher expression of neurotransmitter/G-protein coupled receptors mediated by cAMP and calcium/calmodulin-dependent kinase signaling. Functional implications of these observations were examined using tunicamycin induced ER stress. Wild-type astrocyte stress model showed cell cycle arrest, RIC3 upregulation, reduction in 7nAChR surface levels but increased 4nAChR surface expression. Conversely, tunicamycin treated del astrocytes showed a comparatively higher 4nAChR surface expression and upsurged cAMP signaling. In addition, reduced expression of stress markers CHOP, phospho-PERK and lowered XBP1 splicing in western blot and qPCR, validated by proteome-based pathway analysis indicated lowered disease severity. These findings indicate i) a complex RNA regulatory mechanism via exonic deletion induced splicing; ii) RIC-3 as a disordered protein having contrasting effects on co-expressed nAChR subtypes under basal/stress conditions; and iii) RIC3 as a potential drug target against ER stress in astrocytes for nicotine related brain disorders. Furthermore, cellular rescue mechanism through deletion induced exon skipping possibly opens up ASO based therapies for tauopathies.

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BK, T., Yadav, N.. 2022-07-19. Deletion induced splicing in RIC3 drives nicotinic acetylcholine receptor regulation with implications for endoplasmic reticulum stress in human astrocytes. https://doi.org/10.1101/2022.07.18.500445

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