mRNA Transport und lokale Translation der aktin-bindenden Proteine im Fragile X Syndrom
Molekulare Biologie und Physiologie von Nerven- und Gliazellen
Zellbiologie
Zusammenfassung der Projektergebnisse
Long-lasting modifications of synaptic efficacy of single synapses are believed to represent the cellular correlates of learning and memory formation and depend on the global and local translation of pre-existing mRNAs. These local translation events allow synapses to autonomously and specifically change their structural and functional properties on a rapid time scale, a phenomenon that crucially depends on a fast remodeling of the actin cytoskeleton mediated by actin-binding proteins (ABPs). In the Fragile X Syndrome (FXS), where the Fragile X mental retardation protein 1 (FMRP) as a regulator of mRNA transport and local translation is absent, alterations in synapse structure and function indeed point towards dysregulated actin dynamics. Therefore, this work was aimed at analyzing the role of synaptic actin dynamics and ABPs as an underlying cause of synapse pathology in FXS. We can provide first evidence using Fluorescent In Situ Hybridisation (FISH) experiments that the mRNAs of the ABPs Profilin 1 (Pfn1), Profilin 2a (Pfn2a) and Cofilin 1 (Cof1) are not only localized in dendrites of hippocampal neurons but moreover that ABP mRNA localization is altered in an activity-dependent manner following the induction of long-term potentiation. In addition, Fluorescence Recovery after Photobleaching (FRAP) of membrane-targeted eGFP fused to the 3’UTR of Cof1 revealed that the local translation of Cof1 is modulated by plasticity inducing stimuli as well. Intriguingly, this study shows that in the mouse model of FXS (fmr1 KO), these activity-dependent modulations of ABP mRNAs are absent, and that these defects are additionally accompanied by a complete loss of structural spine plasticity. Most importantly, this structural plasticity defect could be rescued by mimicking Cof1 modulation of WT neurons, thereby directly attributing plasticity deficits in FXS to a dysregulation of ABPs. In summary, this work shows for the first time that the local translation of ABPs is modulated during synaptic plasticity. In addition, this study proposes a causal relationship between dysregulated actin dynamics, derived from alterations in the modulation of local ABP synthesis and local ABP mRNA availability, and synapse pathologies as well as learning deficits in the mouse model of FXS. This findings might be used in the future to target aberrant actin dynamics underlying FXS or even in autism spectrum disorder in general with specific drugs to prevent synapse pathology.
Projektbezogene Publikationen (Auswahl)
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Local translation of actin-binding proteins in the CNS 12th Meeting of the German Neuroscience Society, Göttingen (2017)
Feuge J., Korte M., Michaelsen-Preusse K.
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(2018) Imbalance of synaptic actin dynamics as a key to fragile X syndrome? The Journal of Physiology 596(14):2773-2782
Michaelsen-Preusse K., Feuge J., Korte M.
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Activity-dependent dysregulation of cofilin in the Fragile X Syndrome 10th FENS Forum of Neuroscience, Berlin (2018)
Feuge J., Scharkowski F., Korte M., Michaelsen-Preusse K.
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(2019) FMRP mediates spine plasticity by regulating the localization and local translation of cofilin1 mRNA. Cerebral Cortex bhz059
Feuge J., Scharkowski F., Michaelsen-Preusse K., Korte M.
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Activity-dependent dysregulation of cofilin in the Fragile X Syndrome 13th Meeting of the German Neuroscience Society, Göttingen (2019)
Feuge J., Scharkowski F., Korte M., Michaelsen-Preusse K.
