OBJECTIVE: Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in >40% of individuals with MS. How demyelination alters neuronal gene expression is unknown. METHODS: To explore whether loss of hippocampal myelin alters expression of neuronal microRNAs (miRNAs), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies. RESULTS: A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124 was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors AMPA2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors, and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes. INTERPRETATION: We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MS patients.
OBJECTIVE:Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in >40% of individuals with MS. How demyelination alters neuronal gene expression is unknown. METHODS: To explore whether loss of hippocampal myelin alters expression of neuronal microRNAs (miRNAs), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies. RESULTS: A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124 was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors AMPA2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors, and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes. INTERPRETATION: We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MSpatients.
Authors: Ursula Fünfschilling; Lotti M Supplie; Don Mahad; Susann Boretius; Aiman S Saab; Julia Edgar; Bastian G Brinkmann; Celia M Kassmann; Iva D Tzvetanova; Wiebke Möbius; Francisca Diaz; Dies Meijer; Ueli Suter; Bernd Hamprecht; Michael W Sereda; Carlos T Moraes; Jens Frahm; Sandra Goebbels; Klaus-Armin Nave Journal: Nature Date: 2012-04-29 Impact factor: 49.962
Authors: Sébastien S Hébert; Katrien Horré; Laura Nicolaï; Aikaterini S Papadopoulou; Wim Mandemakers; Asli N Silahtaroglu; Sakari Kauppinen; André Delacourte; Bart De Strooper Journal: Proc Natl Acad Sci U S A Date: 2008-04-23 Impact factor: 11.205
Authors: N L Sicotte; K C Kern; B S Giesser; A Arshanapalli; A Schultz; M Montag; H Wang; S Y Bookheimer Journal: Brain Date: 2008-04 Impact factor: 13.501
Authors: Jacqueline K Morris; Anthony Chomyk; Ping Song; Nate Parker; Sadie Deckard; Bruce D Trapp; Sanjay W Pimplikar; Ranjan Dutta Journal: Invert Neurosci Date: 2015-07-10