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Dicer Is Involved in Cytotoxicity and Motor Impairment Induced by TBPH Deficiency

Xiang Long1, Yijie Wang1, Hongrui Meng1

  • 1Institute of Neuroscience, Soochow University, Suzhou 215123, China.

Current Issues in Molecular Biology
|July 23, 2025
PubMed

Insights

TDP-43 protein regulates microRNA (miRNA) biogenesis genes, impacting motor function and cell damage in ALS models. This study reveals TBPH

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • TDP-43 protein is implicated in amyotrophic lateral sclerosis (ALS).
  • The precise role of TDP-43 in microRNA (miRNA) biogenesis remains unclear.
  • Investigating TDP-43's homolog in Drosophila, TBPH, offers insights into conserved mechanisms.

Purpose of the Study:

  • To elucidate the function of TBPH in regulating miRNA biogenesis genes.
  • To determine the impact of TBPH on Dicer-1 (DCR-1) and Dicer-2 (DCR-2) expression and function.
  • To explore the consequences of TBPH and DCR interactions in a Drosophila model of ALS.

Main Methods:

  • Utilized TBPH knockout and knockdown models in Drosophila.
  • Assessed mRNA transcription and protein levels of DCR-1 and DCR-2.
  • Performed overexpression studies of DCR-1 and DCR-2 in TBPH knockdown backgrounds.
  • Analyzed lifespan, compound eye morphology, and locomotor behavior.
  • Investigated the effects of pharmacological Dicer activation in TBPH-deficient flies.

Main Results:

  • TBPH deficiency significantly reduced DCR-1 and DCR-2 mRNA and protein levels.
  • Overexpression of DCR-1/DCR-2 in TBPH knockdown exacerbated eye damage in a sex-dependent manner.
  • Neuronal TBPH knockdown shortened lifespan, with distinct sex-specific survival curves.
  • DCR-1/DCR-2 knockdown worsened locomotor defects in TBPH-deficient flies.
  • Pharmacological Dicer activation in TBPH-deficient flies induced reverse locomotion.

Conclusions:

  • TBPH is a critical regulator of DCR protein expression, essential for normal miRNA biogenesis.
  • TBPH's role in DCR regulation is conserved and linked to motor function deficits and cytotoxicity in ALS-like pathology.
  • Dysregulation of miRNA biogenesis by TDP-43/TBPH contributes to neurodegenerative processes in ALS.
Keywords:
DicerDrosophilaTBPHamyotrophic lateral sclerosis

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