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Related Concept Videos

Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

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The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
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Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
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mRNA Stability and Gene Expression02:51

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The structure and stability of mRNA molecules regulates gene expression, as mRNAs are a key step in the pathway from gene to protein. In eukaryotes, the half-life of mRNA varies from a few minutes up to several days. mRNA stability is essential in growth and development. The absence of the proteins regulating its stability, such as tristetraprolin in mice, can cause systemic issues, including bone marrow overgrowth, inflammation, and autoimmunity.
Cis-acting Elements involved in mRNA stability
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Chromatin Structure Regulates pre-mRNA Processing02:41

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In eukaryotic cells, nascent mRNA transcripts need to undergo many post-transcriptional modifications to reach the cell cytoplasm and translate into functional proteins. For a long time, transcription and pre-mRNA processing were considered two independent events that occur sequentially in the cell. However, it has now been well established that transcription and pre-mRNA processing are two simultaneous processes that are precisely regulated inside the cell.
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Calmodulin-dependent Signaling01:16

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Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
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Regulation of Expression Occurs at Multiple Steps02:24

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Gene expression can be regulated at almost every step from gene to protein. Transcription is the step that is most commonly regulated. This involves the binding of proteins to short regulatory sequences on the DNA. This association can either promote or inhibit the transcription of a gene associated with the respective sequence.
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Calpain-2 Mediates MBNL2 Degradation and a Developmental RNA Processing Program in Neurodegeneration.

Lee-Hsin Wang1,2, Chien-Yu Lin2, Yu-Mei Lin2

  • 1Taiwan International Graduate Program in Interdisciplinary Neuroscience, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, 11529, Taiwan.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|May 23, 2022
PubMed
Summary

Neurodegenerative diseases involve common pathways. Calpain-2 degrades MBNL2, reverting RNA processing to developmental patterns, a mechanism seen in myotonic dystrophy and Alzheimer's disease models.

Keywords:
Alzheimer's diseaseMBNL2RNA-processingcalpain-2excitotoxicitymyotonic dystrophy

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Neurologic diseases share common degenerative features despite distinct causes.
  • Myotonic dystrophy type 1 (DM1) involves MBNL2 downregulation and aberrant splicing.
  • The role of MBNL2 loss and its regulation in neurodegeneration is unclear.

Purpose of the Study:

  • Investigate the role of MBNL2 in neuronal development and neurodegeneration.
  • Identify the mechanism causing MBNL2 downregulation in neurodegenerative conditions.
  • Determine if calpain-2 mediates MBNL2 degradation in disease models.

Main Methods:

  • Studied MBNL2 expression during neuronal maturation.
  • Induced neurodegeneration using NMDA receptor excitotoxicity and calcium dysregulation.
  • Utilized calpain-2 knockdown and translocation inhibition.
  • Examined MBNL2 and RNA processing in DM1 and Alzheimer's disease mouse models.

Main Results:

  • MBNL2 expression increases with neuronal maturation and is crucial for development.
  • Neurodegeneration triggers calpain-2 nuclear translocation, leading to MBNL2 degradation.
  • Calpain-2 inhibition prevents MBNL2 loss and aberrant RNA processing.
  • This pathway is conserved in DM1 and AD models.

Conclusions:

  • Calpain-2-mediated MBNL2 degradation is a novel mechanism in neurodegeneration.
  • Reversal of RNA processing to developmental patterns contributes to neurodegeneration.
  • Targeting calpain-2 offers a potential therapeutic strategy for neurologic diseases.