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Article type: Research Article
Authors: Gu, Jianlana; b; c; * | Chu, Dandana | Jin, Nanaa | Chen, Fenga; c | Liu, Feic; *
Affiliations: [a] Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China | [b] Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu, China | [c] Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA
Correspondence: [*] Correspondence to: Fei Liu, Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY, USA. Tel.: +1 7184945263; Fax: +1 7184941080; E-mail: feiliu63@hotmail.com and Jianlan Gu, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China. Tel.: +86 51385051813; Fax: +86 51385511585; E-mail: ntgjlan@163.com.
Abstract: Trans-active response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved and ubiquitously expressed nuclear protein. As a member of heterogeneous ribonucleoproteins, TDP-43 plays pivotal roles in mRNA processing. We recently found that TDP-43 promoted tau mRNA instability via acting on the 3’-untranslated region of its mRNA and enhanced tau exon 10 inclusion. TDP-43 is a phospho-protein. The function and the pathological aggregation of TDP-43 are regulated by the phosphorylation. In the present study, we determined phosphorylation of TDP-43 by cyclic AMP-dependent protein kinase (PKA). We found that TDP-43 was co-immunoprecipitated by and co-localized with PKA in the nucleus. PKA phosphorylated TDP-43 at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells. Phosphorylation of TDP-43 at these sites enhanced mutually their phosphorylation by PKA in vitro and in cultured cells. Overexpression of PKA suppressed TDP-43’s activity in promoting tau mRNA instability and tau exon 10 inclusion. These findings shed light on the role of PKA in phosphorylation and function of TDP-43. Downregulation of PKA signaling in AD brain may attenuate the impact of TDP-43 pathology in tau pathogenesis.
Keywords: mRNA processing, phosphorylation, PKA, tau, TDP-43
DOI: 10.3233/JAD-190368
Journal: Journal of Alzheimer's Disease, vol. 70, no. 4, pp. 1093-1102, 2019
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