Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky
Erscheinungsjahr:
2020
Medientyp:
Text
Schlagworte:
Exzitotoxizität
Neurodegeneration
Glutamat
Experimentelle autoimmune Enzephalomyelitis
Neuroinflammation
ZNS-Inflammation
Excitotoxicity
Neurodegeneration
Glutamate
Experimental autoimmune encephalomyelitis
motor neuron
Neuroinflammation
CNS-inflammation
570: Biowissenschaften, Biologie
42.13: Molekularbiologie
42.15: Zellbiologie
42.17: Allgemeine Physiologie
42.20: Genetik
44.90: Neurologie
Multiple Sklerose
miRNA
Motoneuron
Degeneration
Zentralnervensystem
ddc:570:
Multiple Sklerose
miRNA
Motoneuron
Degeneration
Zentralnervensystem
Beschreibung:
Multiple sclerosis (MS) is characterized by immune cell infiltration, axonal demyelination and neurodegeneration. Excessive activation of the glutamatergic pathway accompanies MS pathophysiology resulting in neuronal stress response networks with alteration of neuronal signaling, thereby perpetuating neurodegeneration and consecutive neurological deficits. A fundamental mechanism to respond to changes in the cellular environment is coordination of translation by microRNAs (miRNAs). However, it remains unclear to which extend miRNAs orchestrate neuronal gene expression and determine consecutive neurodegeneration in central nervous system (CNS)-inflammation. By targeted profiling of neuronal transcriptome and miRNome in CNS-inflammation it was demonstrated here that genes involved in neuronal regulatory processes and synaptic signaling were significantly underrepresented, while at the same time newly identified inflammation-induced miRNAs were predicted to target these mRNA transcripts. It was shown in this work that miR-92a-3p was highly expressed in healthy motor neurons and transcriptionally upregulated by extracellular glutamate. Luciferase reporter assays validated cytoplasmic polyadenylation element-binding protein 3 (Cpeb3) mRNA as a miR-92a-3p target. Further, deletion of miR-92a-3p in the MS mouse model experimental autoimmune encephalomyelitis (EAE) led to exacerbated neurological disability but unchanged immune cell infiltration, implying a neuronal function of miR-92a-3p induction. Yet, the neuronal substrate of miR-92a-3p deletion that caused exacerbated clinical disability in CNS-inflammation is still to be investigated. In future studies, the interaction network of miR-92a-3p and Cpeb3 and their implications for neuronal survival in CNS-inflammation and glutamate excitotoxicity will be investigated in mouse models and validated in MS patients. Together, this work offers a new approach for deciphering the contribution of miRNA networks to synaptic function and neuronal integrity in CNS-inflammation with possible implications for the treatment of MS-associated neurodegeneration.