Amyloid peptide exerts a rapid induction of Dicer1 protein in neuron via reducing phosphorylation
Yan Wang1, Xiaoyu Xiu1, Shengzhou Wu1
1School of Optometry and Ophthalmology and the Eye Hospital, Wenzhou Medical University, PR China; State Key Laboratory of Optometry, Ophthalmology, and Visual Science, 270 Xueyuan Road, Wenzhou, Zhejiang, 325003, PR China.
Abstract:
A growing number of evidence suggests that altered microRNA network in the brain contributes to the risk of Alzheimer's disease(AD). Dicer1 is a type III riboendonuclease which cleaves pre-microRNA into functional microRNA. Reduction of Dicer1 or Dicer1 mutation has been involved in cancer, aging or age-related macular degeneration. Recently, we found a possible link between Dicer1 and AD. In particular, Dicer1 protein and Dicer1 mRNA is reduced in the hippocampus and the cortex of an animal model of AD and exposure to Aβ42 oligomer(AβO) longer than 6 h reduces the transcription of Dicer1 gene in neuron, via depletion of NF-E2-related factor-2. In this study, exposure to AβO at shorter time increased Dicer1 protein in neuron in a dose-dependent mode; but the mRNA level remained unaltered. Under this treatment regime,AβO reduced phosphorylation level of Dicer1 and of its binding partner, transactivation response element RNA-binding protein(TRBP). Addition of a JNK inhibitor,SP600125, or an ERK inhibitor,U0126, further increased Dicer1 protein compared to Aβo treatment alone, with simultaneaous reduction of phospho-Dicer1, but with different effects on phospho-TRBP. Finally, an inhibitor of calcineurin,FK506, further increased Dicer1 protein compared to Aβo treatment alone. Thus, phosphorylation of Dicer1 and TRBP was determined by mitogen activated protein kinases JNK,ERK, and protein phosphatase 2B(calcineurin) which together determined Dicer1 stability. In summary, reduced phosphorylation of Dicer1 accounted for the rapid induction of Dicer1 by AβO. This study highlights a novel way by which AβO regulates Dicer1.
Insights
Alzheimer's disease (AD) risk is linked to brain microRNA changes. Amyloid-beta oligomers (AβO) rapidly increase Dicer1 protein in neurons by reducing its phosphorylation, revealing a novel regulatory mechanism.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Altered microRNA networks are implicated in Alzheimer's disease (AD) pathogenesis.
- Dicer1, crucial for microRNA biogenesis, is reduced in AD models.
- Amyloid-beta oligomers (AβO) are key players in AD, affecting neuronal function.
Purpose of the Study:
- To investigate the rapid effects of AβO on Dicer1 protein levels and stability in neurons.
- To elucidate the molecular mechanisms underlying AβO-induced Dicer1 regulation.
- To identify signaling pathways that modulate Dicer1 phosphorylation and stability.
Main Methods:
- Primary neuron cultures were treated with varying concentrations and durations of AβO.
- Western blotting was used to assess Dicer1 and phosphorylated Dicer1/TRBP levels.
- Specific inhibitors (JNK, ERK, calcineurin) were employed to dissect signaling pathways.
Main Results:
- Short-term AβO exposure dose-dependently increased neuronal Dicer1 protein without altering mRNA levels.
- AβO treatment reduced phosphorylation of Dicer1 and its binding partner TRBP.
- Inhibitors of JNK, ERK, and calcineurin further increased Dicer1 protein, indicating their role in regulating Dicer1 stability via phosphorylation.
Conclusions:
- Reduced phosphorylation of Dicer1, mediated by JNK, ERK, and calcineurin, explains the rapid increase in Dicer1 protein induced by AβO.
- This study uncovers a novel mechanism of AβO-mediated regulation of Dicer1, impacting microRNA processing in AD.
- Targeting these signaling pathways may offer new therapeutic strategies for AD.
