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The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells.
Biol Psychiatry 2019; 86(2):120-130BP

Abstract

BACKGROUND

The 5'-nucleotidase, cytosolic II gene (NT5C2, cN-II) is associated with disorders characterized by psychiatric and psychomotor disturbances. Common psychiatric risk alleles at the NT5C2 locus reduce expression of this gene in the fetal and adult brain, but downstream biological risk mechanisms remain elusive.

METHODS

Distribution of the NT5C2 protein in the human dorsolateral prefrontal cortex and cortical human neural progenitor cells (hNPCs) was determined using immunostaining, publicly available expression data, and reverse transcriptase quantitative polymerase chain reaction. Phosphorylation quantification of adenosine monophosphate-activated protein kinase (AMPK) alpha (Thr172) and ribosomal protein S6 (Ser235/Ser236) was performed using Western blotting to infer the degree of activation of AMPK signaling and the rate of protein translation. Knockdowns were induced in hNPCs and Drosophila melanogaster using RNA interference. Transcriptomic profiling of hNPCs was performed using microarrays, and motility behavior was assessed in flies using the climbing assay.

RESULTS

Expression of NT5C2 was higher during neurodevelopment and was neuronally enriched in the adult human cortex. Knockdown in hNPCs affected AMPK signaling, a major nutrient-sensing mechanism involved in energy homeostasis, and protein translation. Transcriptional changes implicated in protein translation were observed in knockdown hNPCs, and expression changes to genes related to AMPK signaling and protein translation were confirmed using reverse transcriptase quantitative polymerase chain reaction. The knockdown in Drosophila was associated with drastic climbing impairment.

CONCLUSIONS

We provide an extensive neurobiological characterization of the psychiatric risk gene NT5C2, describing its previously unknown role in the regulation of AMPK signaling and protein translation in neural stem cells and its association with Drosophila melanogaster motility behavior.

Authors+Show Affiliations

Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.Department of Biological Sciences, Columbian College of Arts and Sciences, George Washington University, Washington, DC.Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Medical Research Council Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.Medical Research Council London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Medical Research Council Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.Department of Biological Sciences, Columbian College of Arts and Sciences, George Washington University, Washington, DC.Medical Research Council London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.Division of Infectious Diseases, Weill Cornell Medicine, Cornell University, New York, New York.Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff, United Kingdom.Department of Biological Sciences, Columbian College of Arts and Sciences, George Washington University, Washington, DC.Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Medical Research Council Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom.Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom.Department of Basic & Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom; Medical Research Council Centre for Neurodevelopmental Disorders, King's College London, London, United Kingdom. Electronic address: deepak.srivastava@kcl.ac.uk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31097295

Citation

Duarte, Rodrigo R R., et al. "The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells." Biological Psychiatry, vol. 86, no. 2, 2019, pp. 120-130.
Duarte RRR, Bachtel ND, Côtel MC, et al. The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells. Biol Psychiatry. 2019;86(2):120-130.
Duarte, R. R. R., Bachtel, N. D., Côtel, M. C., Lee, S. H., Selvackadunco, S., Watson, I. A., ... Srivastava, D. P. (2019). The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells. Biological Psychiatry, 86(2), pp. 120-130. doi:10.1016/j.biopsych.2019.03.977.
Duarte RRR, et al. The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells. Biol Psychiatry. 2019 Jul 15;86(2):120-130. PubMed PMID: 31097295.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Psychiatric Risk Gene NT5C2 Regulates Adenosine Monophosphate-Activated Protein Kinase Signaling and Protein Translation in Human Neural Progenitor Cells. AU - Duarte,Rodrigo R R, AU - Bachtel,Nathaniel D, AU - Côtel,Marie-Caroline, AU - Lee,Sang H, AU - Selvackadunco,Sashika, AU - Watson,Iain A, AU - Hovsepian,Gary A, AU - Troakes,Claire, AU - Breen,Gerome D, AU - Nixon,Douglas F, AU - Murray,Robin M, AU - Bray,Nicholas J, AU - Eleftherianos,Ioannis, AU - Vernon,Anthony C, AU - Powell,Timothy R, AU - Srivastava,Deepak P, Y1 - 2019/03/30/ PY - 2018/01/27/received PY - 2019/02/12/revised PY - 2019/03/11/accepted PY - 2019/5/18/pubmed PY - 2019/5/18/medline PY - 2019/5/18/entrez KW - AMP-activated protein kinase (AMPK) KW - Drosophila melanogaster KW - Functional genetics KW - Neural stem cells KW - Psychiatric disorders KW - Ribosomal protein S6 (RPS6) SP - 120 EP - 130 JF - Biological psychiatry JO - Biol. Psychiatry VL - 86 IS - 2 N2 - BACKGROUND: The 5'-nucleotidase, cytosolic II gene (NT5C2, cN-II) is associated with disorders characterized by psychiatric and psychomotor disturbances. Common psychiatric risk alleles at the NT5C2 locus reduce expression of this gene in the fetal and adult brain, but downstream biological risk mechanisms remain elusive. METHODS: Distribution of the NT5C2 protein in the human dorsolateral prefrontal cortex and cortical human neural progenitor cells (hNPCs) was determined using immunostaining, publicly available expression data, and reverse transcriptase quantitative polymerase chain reaction. Phosphorylation quantification of adenosine monophosphate-activated protein kinase (AMPK) alpha (Thr172) and ribosomal protein S6 (Ser235/Ser236) was performed using Western blotting to infer the degree of activation of AMPK signaling and the rate of protein translation. Knockdowns were induced in hNPCs and Drosophila melanogaster using RNA interference. Transcriptomic profiling of hNPCs was performed using microarrays, and motility behavior was assessed in flies using the climbing assay. RESULTS: Expression of NT5C2 was higher during neurodevelopment and was neuronally enriched in the adult human cortex. Knockdown in hNPCs affected AMPK signaling, a major nutrient-sensing mechanism involved in energy homeostasis, and protein translation. Transcriptional changes implicated in protein translation were observed in knockdown hNPCs, and expression changes to genes related to AMPK signaling and protein translation were confirmed using reverse transcriptase quantitative polymerase chain reaction. The knockdown in Drosophila was associated with drastic climbing impairment. CONCLUSIONS: We provide an extensive neurobiological characterization of the psychiatric risk gene NT5C2, describing its previously unknown role in the regulation of AMPK signaling and protein translation in neural stem cells and its association with Drosophila melanogaster motility behavior. SN - 1873-2402 UR - https://www.unboundmedicine.com/medline/citation/31097295/The_Psychiatric_Risk_Gene_NT5C2_Regulates_Adenosine_Monophosphate-Activated_Protein_Kinase_Signaling_and_Protein_Translation_in_Human_Neural_Progenitor_Cells L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-3223(19)31148-5 DB - PRIME DP - Unbound Medicine ER -