Journal
CHEMBIOCHEM
Volume 22, Issue 2, Pages 349-353Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.202000513
Keywords
gene expression; i-motif; major depressive disorder; nucleic acids; serotonin transporter
Funding
- New Zealand Neurological Foundation
- Victoria University of Wellington
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Neuropsychiatric disorders such as major depressive disorder (MDD) involve a complex interplay of genetic and environmental factors, with the polymorphic region of the serotonin transporter (SERT) potentially playing a role in transcriptional regulation through i-motif formation.
Neuropsychiatric disorders such as major depressive disorder (MDD) arise from a complex set of genetic and environmental factors. The serotonin transporter (SERT) is a key regulator of synaptic serotonin (5-HT), and its inhibition is an important pharmacological target for treating MDD. The SERT-linked polymorphic region (5-HTTLPR) contains two major variants (short and long) that have been implicated in modulating susceptibility to MDD by altering the level of expression of SERT. Both variants contain C-rich repeats that conform to consensus i-motif folding sequences. i-Motifs are quadruplex DNA structures that have been proposed to have a role in transcription regulation. With spectroscopic techniques, we demonstrate that both alleles are able to form i-motifs at acidic pH, and at neutral pH under conditions of molecular crowding. This highlights the potential for i-motif formation to contribute to transcriptional regulation of the serotonin transporter, with a potential role in the pathophysiology of neuropsychiatric disorders.
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