Neurodegeneration induces a developmental RNA processing program by calpain-mediated MBNL2 degradation

Wang, L.-H.; Lin, Y.-M.; Lin, C.-Y.; Chern, Y.; Wang, G.-S.

doi:10.1101/2020.07.24.219121

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bioRxiv · 10.1101/2020.07.24.219121

Neurodegeneration induces a developmental RNA processing program by calpain-mediated MBNL2 degradation

Wang, L.-H.·Lin, Y.-M.·Lin, C.-Y.·Chern, Y.·Wang, G.-S.

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Abstract

The Muscleblind-like (MBNL) protein family plays an important role in regulating developmental RNA processing transition. Loss of MBNL2 function has been implicated in the neurodegeneration of myotonic dystrophy type 1 (DM1). However, the causal mechanism of neurodegeneration-induced MBNL2 loss of function remains elusive. Here, we show that neurodegenerative conditions including NMDAR-mediated excitotoxicity and dysregulated calcium homeostasis triggered nuclear translocation of calpain-2 resulting in MBNL2 degradation and reversion of MBNL2-regulated RNA processing to developmental patterns. The developmental stage featured nucleus-enriched distribution of calpain-2 and low expression of MBNL2. Increased MBNL2 expression during development is required for promoting developmental RNA processing transition and neuronal maturation. Knockdown of calpain-2 expression inhibited neurodegeneration-induced MBNL2 reduction and dysregulated RNA processing. Neurodegenerative disease mouse models including DM1 and Alzheimers disease showed nuclear translocation of calpain-2 associated with MBNL2 degradation and reversion of MBNL2-regulated RNA processing to the developmental pattern. Our results identify a novel regulatory mechanism for MBNL2 downregulation and suggest that reduced MBNL2 expression accompanied by the re-induction of a developmental RNA processing program may be a common feature of neurodegeneration.

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Wang, L.-H., Lin, Y.-M., Lin, C.-Y., Chern, Y., Wang, G.-S.. 2020-07-25. Neurodegeneration induces a developmental RNA processing program by calpain-mediated MBNL2 degradation. https://doi.org/10.1101/2020.07.24.219121

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