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Published on: June 12, 2018
Vulnerability of microRNA biogenesis in FTD-ALS
1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
Abstract:
The genetics of the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) turn our attention to RNA metabolism, primarily because many of the identified diseases-associated genes encode for RNA-binding proteins. microRNAs (miRNAs) are endogenous noncoding RNAs that play critical roles in maintaining brain integrity. The current review sheds light on miRNA dysregulation in neurodegenerative diseases, focusing on FTD-ALS. We propose that miRNAs are susceptible to fail when protein factors that are critical for miRNA biogenesis malfunction. Accordingly, potential insufficiencies of the 'microprocessor' complex, the nucleo-cytoplasmic export of miRNA precursors or their processing by Dicer were recently reported. Furthermore, specific miRNAs are involved in the regulation of pathways that are essential for neuronal survival or function. Any change in the expression of these specific miRNAs or in their ability to recognize their target sequences will have negative consequences. Taken together, recent reports strengthens the hypothesis that dysregulation of miRNAs might play an important role in the pathogenesis of neurodegenerative diseases, and highlights the miRNA biogenesis machinery as an interesting target for therapeutic interventions for ALS as well as FTD. This article is part of a Special Issue entitled SI:RNA Metabolism in Disease.
Insights
Dysregulation of microRNAs (miRNAs) is implicated in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Targeting miRNA biogenesis offers a potential therapeutic avenue for these conditions.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are linked to genetic factors affecting RNA metabolism.
- Many disease-associated genes encode RNA-binding proteins, highlighting the role of RNA processing in neuronal health.
- microRNAs (miRNAs) are crucial noncoding RNAs for maintaining brain integrity.
Purpose of the Study:
- To review the role of miRNA dysregulation in neurodegenerative diseases, with a focus on FTD-ALS.
- To explore the hypothesis that impaired miRNA biogenesis contributes to FTD-ALS pathogenesis.
- To identify the miRNA biogenesis machinery as a potential therapeutic target.
Main Methods:
- Review of current literature on miRNA function and dysregulation in neurodegenerative diseases.
- Analysis of proposed mechanisms for miRNA biogenesis failure, including microprocessor complex dysfunction and Dicer processing issues.
- Examination of the impact of altered miRNA expression on neuronal survival pathways.
Main Results:
- Evidence suggests that malfunctions in protein factors essential for miRNA biogenesis can lead to miRNA failure.
- Reported insufficiencies in the microprocessor complex, miRNA precursor export, and Dicer processing are linked to disease.
- Specific miRNAs regulate critical neuronal pathways, and their altered expression or target recognition has detrimental effects.
Conclusions:
- Dysregulation of miRNAs is strongly implicated in the pathogenesis of neurodegenerative diseases like FTD-ALS.
- The miRNA biogenesis machinery represents a promising target for developing novel therapeutic interventions for ALS and FTD.
- Further research into miRNA pathways could unlock new treatment strategies for these devastating conditions.
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