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
AU - Cotel, 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.
PY - 2019/7/15
Y1 - 2019/7/15
N2 - Genome-wide significant variants associated with combined risk for major psychiatric disorders on chromosome 10q24 affect the expression of the cytosolic nucleotidase II (NT5C2, cN-II) in population controls, implicating it as a psychiatric susceptibility gene. Risk alleles are associated with reduced expression of this gene in the developing and adult brain, but the resulting neurobiological risk mechanisms remain elusive. In this study, we provide further evidence for the association of NT5C2 with psychiatric disorders, and use a functional genetics approach to gain a deeper understanding of the function of this risk gene in the nervous system. NT5C2 expression was significantly reduced in the post-mortem brain of schizophrenia and bipolar disorder patients, and its protein predominately expressed in neurons within the adult brain. Using human neural progenitor cells (hNPCs), we found that NT5C2 expression peaked at the neural progenitor state, where the encoded protein was ubiquitously distributed through the cell. NT5C2 knockdown in hNPCs elicited transcriptomic changes associated with protein translation, that were accompanied by regulation of adenosine monophosphate-activated protein kinase (AMPK) signalling and ribosomal protein S6 (rpS6) activity. To identify the effect of reduced neuronal NT5C2 expression at a systems level, we knockdown its homologue, CG32549, in Drosophila melanogaster CNS. This elicited impaired climbing behaviour in the model organism. Collectively, our data implicate NT5C2 expression in risk for psychiatric disorders and in Drosophila melanogaster motility, and further suggest that risk is mediated via regulation of AMPK signalling and protein translation during early neurodevelopment.
AB - Genome-wide significant variants associated with combined risk for major psychiatric disorders on chromosome 10q24 affect the expression of the cytosolic nucleotidase II (NT5C2, cN-II) in population controls, implicating it as a psychiatric susceptibility gene. Risk alleles are associated with reduced expression of this gene in the developing and adult brain, but the resulting neurobiological risk mechanisms remain elusive. In this study, we provide further evidence for the association of NT5C2 with psychiatric disorders, and use a functional genetics approach to gain a deeper understanding of the function of this risk gene in the nervous system. NT5C2 expression was significantly reduced in the post-mortem brain of schizophrenia and bipolar disorder patients, and its protein predominately expressed in neurons within the adult brain. Using human neural progenitor cells (hNPCs), we found that NT5C2 expression peaked at the neural progenitor state, where the encoded protein was ubiquitously distributed through the cell. NT5C2 knockdown in hNPCs elicited transcriptomic changes associated with protein translation, that were accompanied by regulation of adenosine monophosphate-activated protein kinase (AMPK) signalling and ribosomal protein S6 (rpS6) activity. To identify the effect of reduced neuronal NT5C2 expression at a systems level, we knockdown its homologue, CG32549, in Drosophila melanogaster CNS. This elicited impaired climbing behaviour in the model organism. Collectively, our data implicate NT5C2 expression in risk for psychiatric disorders and in Drosophila melanogaster motility, and further suggest that risk is mediated via regulation of AMPK signalling and protein translation during early neurodevelopment.
KW - AMP-activated protein kinase (AMPK)
KW - Drosophila melanogaster
KW - Functional genetics
KW - Neural stem cells
KW - Psychiatric disorders
KW - Ribosomal protein S6 (RPS6)
UR - http://www.scopus.com/inward/record.url?scp=85065547138&partnerID=8YFLogxK
U2 - 10.1101/468546
DO - 10.1101/468546
M3 - Article
SN - 0006-3223
VL - 86
SP - 120
EP - 130
JO - Biological psychiatry
JF - Biological psychiatry
IS - 2
ER -