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cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.

Diana M Ho1, Muhammad Shaban2,3,4,5, Faisal Mahmood2,3,4,5

  • 1Department of Cell Biology, Harvard Medical School, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|June 5, 2024
PubMed
Summary
This summary is machine-generated.

Modulating the cAMP/PKA pathway, by targeting genes like dunce and PKA-R2, can reduce TDP-43 protein aggregation and mislocalization, ameliorating motor deficits in amyotrophic lateral sclerosis (ALS) models.

Keywords:
ALSTDP-43cAMP/PKA signalingneurodegenerationproteinopathy

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Cytoplasmic mislocalization and aggregation of TDP-43 are key features of amyotrophic lateral sclerosis (ALS).
  • The molecular mechanisms regulating these TDP-43 pathologies remain largely unknown.
  • The phospholipase D (Pld) pathway has been implicated in ALS-related phenotypes.

Purpose of the Study:

  • To identify downstream targets of the Pld pathway involved in TDP-43 regulation.
  • To investigate the role of cAMP/PKA signaling in TDP-43 proteinopathies.
  • To explore therapeutic strategies for ALS by modulating this pathway.

Main Methods:

  • Genome-wide screens in *Drosophila melanogaster* to identify modifiers of *TDP-43* and *FUS*.
  • Genetic knockdown of identified modifier genes (*dunce*, *PKA-R2*) in a *Drosophila* model overexpressing the *TDP-43* ortholog *TBPH*.
  • Assessment of TBPH aggregation and mislocalization in motor neurons.
  • Evaluation of motor function and lifespan in adult flies.

Main Results:

  • The phosphodiesterase *dunce* and the PKA inhibitory subunit *PKA-R2* were identified as modifiers of *TBPH*-induced phenotypes.
  • Knockdown of *dunce* or *PKA-R2* mitigated TBPH aggregation and mislocalization.
  • Reducing *dunce* or *PKA-R2* ameliorated motor defects and extended lifespan in *TBPH* models.
  • PKA kinase activity was found to be downstream of both TBPH and Pld.
  • Overexpression of CrebA, a PKA target, rescued TBPH mislocalization.

Conclusions:

  • The cAMP/PKA signaling pathway is a crucial regulator of TDP-43 aggregation and mislocalization.
  • Enhancing cAMP/PKA signaling offers a potential therapeutic avenue for ALS.
  • Targeting components like *dunce* and *PKA-R2* may ameliorate the molecular and functional consequences of pathological TDP-43.