PT  - JOURNAL ARTICLE
AU  - Lee-Hsin Wang
AU  - Yu-Mei Lin
AU  - Chien-Yu Lin
AU  - Yijuang Chern
AU  - Guey-Shin Wang
TI  - Neurodegeneration induces a developmental RNA processing program by calpain-mediated MBNL2 degradation
AID  - 10.1101/2020.07.24.219121
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.07.24.219121
4099  - http://biorxiv.org/content/early/2020/07/25/2020.07.24.219121.short
4100  - http://biorxiv.org/content/early/2020/07/25/2020.07.24.219121.full
AB  - 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 Alzheimer’s 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.Competing Interest StatementThe authors have declared no competing interest.