TDP-43 suppresses tau expression via promoting its mRNA instability.
In the brains of individuals with Alzheimer's disease (AD) and chronic traumatic encephalopathy, tau pathology is accompanied usually by intracellular aggregation of transactive response DNA-binding protein 43 (TDP-43). However, the role of TDP-43 in tau pathogenesis is not understood. Here, we investigated the role of TDP-43 in tau expression in vitro and in vivo. We found that TDP-43 suppressed tau expression by promoting its mRNA instability through the UG repeats of its 3΄-untranslated region (3΄-UTR). The C-terminal region of TDP-43 was required for this function. Neurodegenerative diseases-causing TDP-43 mutations affected tau mRNA instability differentially, in that some promoted and others did not significantly affect tau mRNA instability. The expression levels of tau and TDP-43 were inverse in the frontal cortex and the cerebellum. Accompanied with cytoplasmic accumulation of TDP-43, tau expression was elevated in TDP-43M337V transgenic mouse brains. The level of TDP-43, which is decreased in AD brains, was found to correlate negatively with the tau level in human brain. Our findings indicate that TDP-43 suppresses tau expression by promoting the instability of its mRNA. Down-regulation of TDP-43 may be involved in the tau pathology in AD and related neurodegenerative disorders.
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.|Department of Biochemistry and molecular biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China.
Jianlan
J
Gu
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Feng
F
Wu
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Wen
W
Xu
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Jianhua
J
Shi
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Wen
W
Hu
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.
Nana
N
Jin
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Biochemistry and molecular biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China.
Wei
W
Qian
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Xinglong
X
Wang
Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Khalid
K
Iqbal
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Cheng-Xin
CX
Gong
Key Laboratory of Neuroregeneration of Jiangsu and ministry of education and Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.|Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
Fei
F
Liu
D020413:3' Untranslated Regions; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002478:Cells, Cultured; D002531:Cerebellum / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005260:Female; D005625:Frontal Lobe / Q000737:chemistry; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics*
D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C000598624:TARDBP protein, human; D016875:tau Proteins