Premium
Activation of the D2 dopamine receptor hampers the protective effect of the A 2A adenosine receptor on TDP‐43 mislocalization
Author(s) -
Chern Yijuang,
Lai ChaYou,
Liu YuJu,
Lai HsingLin
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb140
Subject(s) - neurodegeneration , chemistry , receptor , frontotemporal lobar degeneration , rna splicing , microbiology and biotechnology , rna , biochemistry , biology , frontotemporal dementia , medicine , gene , dementia , disease
TAR DNA‐binding protein (TDP‐43) is an RNA‐binding protein that exists mostly in the nucleus and regulates transcription and RNA splicing. Mislocalization of TDP‐43 to the cytoplasm has been observed in several neurodegeneration diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and is believed to initiate the pathogenesis of TDP‐43 proteinopathy. We have previously published that several adenosine analogues (T1‐11 and its analogues) prevented the reactive oxygen species (ROS)‐induced TDP‐43 mislocalization in a mouse motor neuron cell line (NSC34) via the A 2A adenosine receptor (A 2A R), and prevented the degenerated motor functions in a TDP‐43 transgenic ALS mouse model. In the striatum, previous studies suggest that A 2A R and the D 2 dopamine receptor (D 2 R) formed dimmer and negatively cross‐regulated each other's functions. In the present study, we first demonstrated that A 2A R and D 2 R both exist in the motor neurons of the spinal cord of normal subjects and ALS patients by using immunofluorescence assay. Expression of both A 2A R and D 2 R in NSC34 cells led to dimer formation as assessed using the proximity ligation assay ( in situ PLA). No change in the binding affinity of T1‐11 was observed when A 2A R formed dimmer with D 2 R. Nonetheless, activation of D 2 R reversed the A 2A R‐mediated prevention of ROS‐induced AMPK activation and TDP‐43 mislocalization in NSC34 cells. Given that D 2 R agonists have been commonly used in clinical settings, the impact of D 2 R activation on the normalization of TDP‐43 mislocalization by A 2A R in ALS warrants further investigation.