cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization

• 成果类型: Article
• 署名作者: Ho, Diana M.; Shaban, Muhammad; Mahmood, Faisal; Ganguly, Payel; Todeschini, Leonardo; Van Vactor, David; Artavanis-Tsakonas, Spyros
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14668
• DOI: 10.1073/pnas.2400732121
• 发表日期: 2024-06-11
• 关键词: phospholipase-d; alzheimers-disease; phosphatidic-acid; pde4 inhibitors; drosophila; mutations; dysfunction; protein; complexity; PATHWAY

摘要

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 TDP - 43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS - related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al. , Genetics 215 , 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 dunce and the inhibitory subunit PKA - R2 , as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP - 43 ortholog TBPH . 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.