cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization

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.