Fragile X mental retardation protein regulates synaptic translation of neuroligins

• Autorzy: Podsiadlowska J.J. , Kuzniewska B. , Milek J. , Urbanska K. , Dziembowska M.
• Języki publikacji: EN

Abstrakty

EN

INTRODUCTION: Neuroligins (NLGNs) are postsynaptic cell adhesion proteins which bind to their presynaptic partners neurexins across the synaptic cleft. Thus, NLGNs are crucial for the formation, maturation and maintenance of synapses. In rodents, neuroligins are encoded by four genes: Nlgn1, Nlgn2, Nlgn3 and Nlgn4. The mutations in Nlgn3 and Nlgn4 genes are associated with autistic phenotype. Another cause of autistic behaviors, fragile X syndrome, results from the lack of fragile X mental retardation protein (FMRP). FMRP binds to neuronal mRNAs and regulate local translation of transcripts that play an important role in synaptic signaling and plasticity. AIM(S): We aimed to determine if synaptic translation of Nlgn1, Nlgn2 and Nlgn3 mRNAs is regulated by FMRP. METHOD(S): We used Fmr1 knock-out mice (Fmr1 KO) and their wild type (WT) littermates to isolate synaptoneurosomes, which were stimulated in vitro to induce local protein synthesis. We performed FMRP IP on synaptoneurosomes and FISH combined with FMRP immunostaining on cultured neurons to investigate Nlgns mRNAs interaction with FMRP. The polyribosome fractionation was used to elucidate if FMRP regulates Nlgns mRNAs local translation. To study the surface versus intracellular NLGNs distribution at WT and Fmr1 KO synapses we have chosen chemical crosslinking and biotinylation assays, followed by Western blotting. RESULTS: We show that mRNAs for three studied neuroligins interact directly with FMRP in synaptoneurosomes and Nlgn1, Nlgn2, Nlgn3 mRNAs colocalize with FMRP in dendritic granules of cultured hippocampal neurons. The Nlgn1, Nlgn2 and Nlgn3 mRNAs associate with translating polyribosomes in response to synaptic stimulation and Fmr1 KO mice exhibit upregulated local translation due to the lack of FMRP. Finally, the excessive local synthesis of NLGN proteins at Fmr1 KO synapses leads to their elevated level on the postsynaptic membrane. CONCLUSIONS: Nlgn1, Nlgn2 and Nlgn3 mRNAs are locally translated at the synapse and FMRP regulates this process. FINANCIAL SUPPORT: Supported by NCN grant Sonata Bis 2014/14/E/NZ3/00375.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2017
• Tom: 77
• Numer: Suppl.1
• Opis fizyczny: p.70

Twórcy

autor

Podsiadlowska J.J.

• Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland
• Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

autor

Kuzniewska B.

• Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland

autor

Milek J.

• Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland

autor

Urbanska K.

• Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland

autor

Dziembowska M.

• Laboratory of Molecular Basis of Synaptic Plasticity, Centre of New Technologies, University of Warsaw, Warsaw, Poland