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PDZ Scaffold Protein CAL Couples with Metabotropic Glutamate Receptor 5 to Protect Against Cell Apoptosis and Is a Potential Target in the Treatment of Parkinson's Disease.
Luo, Wen Yuan; Xing, Su Qian; Zhu, Ping; Zhang, Chen Guang; Yang, Hui Min; Van Halm-Lutterodt, Nicholas; Gu, Li; Zhang, Hong.
Afiliação
  • Luo WY; Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China.
  • Xing SQ; Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China.
  • Zhu P; Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China.
  • Zhang CG; Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, 100069, China.
  • Yang HM; Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China.
  • Van Halm-Lutterodt N; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100069, China.
  • Gu L; Department of Orthopaedics and Neurosurgery, Keck Medical Center, University of Southern California, Los Angeles, CA, 90033, USA.
  • Zhang H; Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, 100069, China. guli75@ccmu.edu.cn.
Neurotherapeutics ; 16(3): 761-783, 2019 07.
Article em En | MEDLINE | ID: mdl-31073978
Targeting mGluR5 has been an attractive strategy to modulate glutamate excitotoxicity for neuroprotection. Although human clinical trials using mGluR5 negative allosteric modulators (NAMs) have included some disappointments, recent investigations have added several more attractive small molecules to this field, providing a promise that the identification of more additional strategies to modulate mGluR5 activity might be potentially beneficial for the advancement of PD treatment. Here, we determined the role of the interacting partner CAL (cystic fibrosis transmembrane conductance regulator-associated ligand) in mGluR5-mediated protection in vitro and in vivo. In astroglial C6 cells, CAL deficiency blocked (S)-3, 5-dihydroxyphenylglycine (DHPG)-elicited p-AKT and p-ERK1/2, subsequently prevented group I mGluRs-mediated anti-apoptotic protection, which was blocked by receptor antagonist 1-aminoindan-1, 5-dicarboxylic acid (AIDA), and PI3K or MEK inhibitor LY294002 or U0126. In rotenone-treated MN9D cells, both CAL and mGluR5 expressions were decreased in a time- and dose-dependent manner, and the correlation between these 2 proteins was confirmed by lentivirus-delivered CAL overexpression and knockdown. Moreover, CAL coupled with mGluR5 upregulated mGluR5 protein expression by inhibition of ubiquitin-proteasome-dependent degradation to suppress mGluR5-mediated p-JNK and to protect against cell apoptosis. Additionally, CAL also inhibited rotenone-induced glutamate release to modulate mGluR5 activity. Furthermore, in the rotenone-induced rat model of PD, AAV-delivered CAL overexpression attenuated behavioral deficits and dopaminergic neuronal death, while CAL deficiency aggravated rotenone toxicity. On the other hand, the protective effect of the mGluR5 antagonist MPEP was weakened by knocking down CAL. In vivo experiments also confirmed that CAL inhibited ubiquitination-proteasome-dependent degradation to modulate mGluR5 expression and JNK phosphorylation. Our findings show that CAL protects against cell apoptosis via modulating mGluR5 activity, and may be a new molecular target for an effective therapeutic strategy for PD.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Apoptose / Regulador de Condutância Transmembrana em Fibrose Cística / Domínios PDZ / Receptor de Glutamato Metabotrópico 5 Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Parkinson / Apoptose / Regulador de Condutância Transmembrana em Fibrose Cística / Domínios PDZ / Receptor de Glutamato Metabotrópico 5 Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Ano de publicação: 2019 Tipo de documento: Article