TDP-43 interaction with the intracellular domain of amyloid precursor protein induces p53-associated apoptosis.
TAR DNA-binding protein 43 (TDP-43), an essential pathological protein in both amyotrophic later sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), is expressed abnormally in Alzheimer's disease (AD). However, whether and how TDP-43 contributes the pathogenesis of AD remains unknown. We have shown here a colocalization between TDP-43 and the intracellular domain of APP (AICD) in the nucleus. Coimmunoprecipitation analysis showed an interaction between TDP-43 and AICD. Overexpression of TDP-43 in COS7 cells enhanced the transactivation of AICD in an APP-Gal4 luciferase reporter system. Real-time PCR analysis showed that cotransfection of TDP-43 and AICD in HEK293 cells increased P53 mRNA levels compared to either TDP-43-transfected or AICD-transfected cells. Moreover, cotransfection of TDP-43 and AICD in either N2a or COS7 cells showed increased numbers of apoptotic cells compared to either TDP-43-transfected or AICD-transfected cells, indicating that TDP-43 enhances AICD-mediated apoptosis in N2a or COS7 cells. Thus, TDP-43 may play a role in AD pathology through interaction with AICD.
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, the Second Affiliated Hospital, Soochow University, Suzhou, China.
Jing
J
Wang
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, the Second Affiliated Hospital, Soochow University, Suzhou, China.
Ke
K
Yan
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, the Second Affiliated Hospital, Soochow University, Suzhou, China.
Zhi-Qiang
ZQ
Wu
Affiliated Bayi Brain Hospital, Beijing Military General Hospital, Beijing, China.
Chuan-Yi
CY
Zheng
Affiliated Bayi Brain Hospital, Beijing Military General Hospital, Beijing, China.
Ru-Xiang
RX
Xu
Affiliated Bayi Brain Hospital, Beijing Military General Hospital, Beijing, China.
Li-Hua
LH
Chen
Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Zhong-Min
ZM
Wen
Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
He-Qing
HQ
Zhao
Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, the Second Affiliated Hospital, Soochow University, Suzhou, China. Electronic address: h999.judy@gmail.com.
Quan-Hong
QH
Ma
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53
Alzheimer's disease; Amyloid precursor protein; TAR DNA-binding protein 43; The intracellular domain of APP