cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 24; p. e2400732121
• Main Authors: Ho, Diana M, Shaban, Muhammad, Mahmood, Faisal, Ganguly, Payel, Todeschini, Leonardo, Van Vactor, David, Artavanis-Tsakonas, Spyros
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11.06.2024
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Cyclic AMP; Cyclic AMP - metabolism; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Fruit flies; Genes; Genetics; Humans; Insects; Kinases; Life span; Motor Neurons - metabolism; Phenotypes; Phosphatidic acid; Phospholipase D; Protein kinase A; Signal Transduction; ALS; neurodegeneration; proteinopathy; cAMP/PKA signaling; TDP-43
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2400732121

Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes and have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly [M. W. Kankel , Genetics , 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase and the inhibitory subunit , as modifiers of pathogenic phenotypes resulting from overexpression of the ortholog . We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.