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

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 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.

Retrospective review of Infections in Children with β- Thalassemia

“…The bacterial infections in this cohort study was five episodes only, which amounts 0.23 attack per 100 child per year, this proportion was far less than that found in other cohorts was 2.6 and 1.6 attacks per 100 child per year. [17,18] This disparities may be linked to demographic/ geographical dissimilarities, in addition to the restricted period of the study matched to other studies, Rahav et al [17] informed a substantial increasing of the infection rate over time, especially after 15 years, which is lengthier than period since establishing of thalassemia center in our locality. Sepsis was one of the substantial severe bacterial infection in this study (n=2, 40%), earlier studies [18,19] found less occurrence of septicemia (14-25%) because of variety of infections like liver abscess which was not seen in this study.…”

“…[17,18] This disparities may be linked to demographic/ geographical dissimilarities, in addition to the restricted period of the study matched to other studies, Rahav et al [17] informed a substantial increasing of the infection rate over time, especially after 15 years, which is lengthier than period since establishing of thalassemia center in our locality. Sepsis was one of the substantial severe bacterial infection in this study (n=2, 40%), earlier studies [18,19] found less occurrence of septicemia (14-25%) because of variety of infections like liver abscess which was not seen in this study. Pneumonia comprised 20% of infections within the study, this was nearly consistent with previous studies 26% and 21.4% [17,19].…”

“…On the other hand, many other bacterial infections were recorded in other studies and not experienced by our children like soft-tissue infection, liver abscess, osteomyelitis, enteritis, pulmonary, renal or abdominal abscesses, or gum abscess, retropharynx or buttocks, and fever of unknown origin. [17,18] . Four of the 5 documented infection were developed in non-splenectomized children, which give a rate of (3%) of infection, in splenectomized child, only one infectious attack (pneumonia) was itemized, (1.9%), this was inconsistent with other studies [15,17,20] where they found that the infection rate of thalassemia is augmented by splenectomy (14.7%, 10.2%and 13% respectively).…”