TY - JOUR

T1 - Dysregulated COMT Expression in Fragile X Syndrome

AU - Utami, Kagistia Hana

AU - Yusof, Nur Amirah Binte Muhammed

AU - Garcia-Miralles, Marta

AU - Skotte, Niels Henning

AU - Nama, Srikanth

AU - Sampath, Prabha

AU - Langley, Sarah R.

AU - Pouladi, Mahmoud A.

N1 - Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

PY - 2023

Y1 - 2023

N2 - Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.

AB - Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes for catechol-o-methyltransferase and its association with neuropsychiatric disorders and cognitive function has been extensively studied. We observed a significantly reduced level of COMT in in FXS human neural progenitors and neurons, as well as hippocampal neurons from Fmr1 null mice. We show that deficits in COMT were associated with an altered response in an assay of dopaminergic activity in Fmr1 null mice. These findings demonstrate that loss of FMRP downregulates COMT expression and affects dopamine signaling in FXS, and supports the notion that targeting catecholamine metabolism may be useful in regulating certain neuropsychiatric aspects of FXS.

KW - COMT

KW - Fragile X syndrome

KW - Isogenic stem cell model

KW - Neurons

KW - Proteomics

KW - RNAseq

U2 - 10.1007/s12017-023-08754-1

DO - 10.1007/s12017-023-08754-1

M3 - Journal article

C2 - 37684514

AN - SCOPUS:85170081382

VL - 25

SP - 644

EP - 649

JO - NeuroMolecular Medicine

JF - NeuroMolecular Medicine

SN - 1535-1084

ER -