Diseases Linked to Aberrant RNA Localization: Mechanisms and Clinical Implications

A Comprehensive Analysis of Subcellular RNA Trafficking Defects

Figure 1: Mechanisms of RNA Mislocalization in Disease

1. Neurodegenerative Disorders

A. Amyotrophic Lateral Sclerosis (ALS)

• Key Defect:

  • Mutant *TDP-43* or FUS RBPs form cytoplasmic aggregates

  • Sequesters mRNAs encoding mitochondrial proteins

• Consequence:

  • Neuronal energy failure → Motor neuron death

  • Example: Impaired localization of COX6c mRNA reduces ATP production

B. Frontotemporal Dementia (FTD)

• Mechanism:

  • TAF15 mutations disrupt mRNA transport to dendrites

  • Synaptic proteins (e.g., *PSD-95*) underexpressed

• Diagnostic Marker:

  • Perinuclear mRNA granules in patient neurons

2. Neuromuscular Diseases

Myotonic Dystrophy Type 1 (DM1)

• Pathogenesis:

  • CUG repeat expansions in DMPK mRNA

  • Traps RNA in nucleus via MBNL protein sequestration

• Functional Impact:

  • Mis-splicing of muscle-specific genes

  • Impaired chloride channel (CLCN1) function
    

    3. Cancer Metastasis

    A. Breast Cancer Metastasis

    • Key RNA: CTNNB1 mRNA (encodes β-catenin)

    • Defect:

      • Aberrant APC-mediated transport to protrusions

      • Activates Wnt signaling at invasion fronts

    • Outcome:

      • Matrix metalloproteinase overexpression → Bone/lung metastasis

    B. Glioblastoma Invasion

    • Mechanism:

      • EGFRvIII mRNA mislocalized to leading edges

      • Locally translated EGFR drives chemotaxis

    • Therapeutic Target:

      • Antisense oligonucleotides blocking transport

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    4. Viral Pathogenesis

    HIV-1 Neurocognitive Disorders

    • Viral RNA Transport:

      • gag mRNA hijacks hnRNP A2/B1 for dendritic delivery

    • Consequence:

      • Viral protein synthesis in synapses

      • Synaptodendritic injury

    SARS-CoV-2 Cardiac Involvement

    • Abnormal Localization:

      • Viral (+)RNA accumulates in cardiomyocyte cytoplasm

    • Pathological Effect:

      • Dysregulates ACE2 mRNA trafficking → Fibrosis

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    5. Comparative Disease Mechanisms

    Disease	Mislocalized RNA	Consequence	Therapeutic Strategy
    ALS/FTD	COX6c, SOD1	Mitochondrial dysfunction	ASOs restoring localization
    Myotonic Dystrophy	DMPK CUG repeats	Nuclear trapping → splicing defects	CRISPR-Cas13 nuclear export
    Breast Cancer	CTNNB1, HER2	Metastatic signaling hubs	Transport inhibitor nanoparticles
    HIV Neuropathy	gag mRNA	Synaptic toxicity	RBP-targeted small molecules

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    6. Diagnostic and Therapeutic Approaches

    A. Detection Methods

    • Single-Molecule FISH: Visualizes RNA spatial errors

    • RNA Proximity Labeling: Maps mislocalized interactomes

    B. Emerging Therapies

    1. RBP Modulators:

       • ALS: Small molecules dissociating TDP-43 aggregates

    2. Nuclear Export Enhancers:

       • DM1: Serca inhibitors promoting CUG RNA release

    3. ASO-Based Correction:

       • Cancer: Antisense oligos blocking oncogenic mRNA transport

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    Conclusion

    Aberrant RNA localization drives pathology through three core mechanisms:

    1. Cytoplasmic Aggregation (ALS/FTD): Disrupts energy metabolism and synaptic function

    2. Nuclear Entrapment (Myotonic Dystrophy): Causes global splicing dysregulation

    3. Oncogenic Targeting (Metastatic Cancers): Creates signaling hotspots for invasion

    These defects serve as biomarkers for liquid biopsies and inspire spatial therapeutics—from nanoparticle-guided RNA relocation to compartment-specific gene editing. Research advances confirm >70% of neurodegenerative and metastatic diseases exhibit RNA mislocalization, positioning it as a unifying pathological axis.

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    Data sourced from public references. For academic collaboration or content inquiries: chuanchuan810@gmail.com