Regulation of glutamate transporter trafficking by Nedd4-2 in a Parkinson's disease model.
Glutamate transporters play a key role in glutamate clearance and protect the central nervous system from glutamate excitotoxicity. Dysfunctional glutamate transporters contribute to the pathogenesis of Parkinson's disease (PD); however, the mechanisms that underlie the regulation of glutamate transporters in PD are still not well characterized. Here we report that Nedd4-2 mediates the ubiquitination of glutamate transporters in 1-methyl-4- phenylpyridinium (MPP+)-treated astrocytes and in the midbrain of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP)-constructed PD model mice. Nedd4-2-mediated ubiquitination induces abnormal glutamate transporter trafficking between the membrane and cytoplasm and consequently decreases the expression and function of glutamate transporters in the membrane. Conversely, Nedd4-2 knockdown decreases glutamate transporter ubiquitination, promotes glutamate uptake and increases glutamate transporter expression in vitro and in vivo. We report for the first time that Nedd4-2 knockdown ameliorates movement disorders in PD mice and increases tyrosine hydroxylase expression in the midbrain and striatum of PD mice; Nedd4-2 knockdown also attenuates astrogliosis and reactive microgliosis in the MPTP model that may be associated with glutamate excitotoxicity. Furthermore, the SGK/PKC pathway is regulated downstream of Nedd4-2 in MPTP-treated mice. These findings indicate that Nedd4-2 may serve as a potential therapeutic target for the treatment of PD.
Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China.
Yunlong
Y
Zhang
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xiaoliang
X
He
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xingjun
X
Meng
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xiaojuan
X
Wu
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Huichun
H
Tong
Teaching Center of Experimental Medicine, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Xiuping
X
Zhang
Department of Neurology, The First People's Hospital of Shunde Affiliated to Southern Medical University, Foshan, Guangdong 528300, China.
Shaogang
S
Qu
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology; D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000075702:Nedd4 Ubiquitin Protein Ligases; D010300:Parkinson Disease / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D027322:Amino Acid Transport System X-AG; D056827:Endosomal Sorting Complexes Required for Transport; D018698:Glutamic Acid; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D011493:Protein Kinase C; D015655:1-Methyl-4-phenylpyridinium