Dynamics of local presynaptic protein synthesis of active zone components in spinal motoneurons
Final Report Abstract
Local protein synthesis in axon terminals plays a central role in axon guidance, postnatal differentiation of active zones and possibly also in synaptic plasticity of neuromuscular endplates. We found that axon terminals of motoneurons contain high levels of ribosomal subunits, and that these ribosomal subunits assemble in an actin dependent manner within seconds after stimulation with brain-derived neurotrophic factor (BDNF). Moreover, these ribosomes are associated with endoplasmatic reticulum (ER), and ribosomes assemble at ER- like structures after BDNF stimuli which allows synthesis of membrane proteins close to presynaptic active zones in axon terminals of motoneurons. The analysis of axonal transcriptomes from embryonic motoneurons from a mouse model of spinal muscular atrophy (SMA) revealed reduced axonal transcript levels of Munc13-1 mRNA but not mRNAs for other synaptic components such as synaptophysin. We found that these alterations correlate with a specific deficiency of Munc13-1 protein in presynaptic zones that apparently causes defective release of synaptic vesicles. Reduced axonal transcript levels for Munc13-1 can be normalized in the SMA cell culture model by a chimeric Munc13-1 transcript with a heterologous 3´UTR derived from the transcript for synaptophysin, but not by Munc13-1 overexpression lacking this 3´UTR. Expression of this chimaeric transcript rescues the disease phenotype in cultured Smn deficient motoneurons and in a new mouse model of SMA in which this construct is conditionally expressed in neuronal cells. This novel construct could be used as a new strategy for therapy of synaptic defects in SMA, the predominant form of motoneuron disease in children and young adults. Our results also indicate that the mRNA transport mechanism for translocation of the Munc13-1 transcript into axons is defective in SMA, whereas the transport for transcripts such as synaptophysin is unaffected. In summary, these results indicate that Munc13-1 is locally synthesized at presynaptic active zones in axon terminals of motoneurons, and that this cellular mechanism is defective in SMA.
Publications
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Dynamic remodeling of ribosomes and endoplasmic reticulum in axon terminals of motoneurons. Journal of Cell Science, 134(22).
Deng, Chunchu; Moradi, Mehri; Reinhard, Sebastian; Ji, Changhe; Jablonka, Sibylle; Hennlein, Luisa; Lüningschrör, Patrick; Doose, Sören; Sauer, Markus & Sendtner, Michael
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Impaired dynamic interaction of axonal endoplasmic reticulum and ribosomes contributes to defective stimulus–response in spinal muscular atrophy. Translational Neurodegeneration, 11(1).
Deng, Chunchu; Reinhard, Sebastian; Hennlein, Luisa; Eilts, Janna; Sachs, Stefan; Doose, Sören; Jablonka, Sibylle; Sauer, Markus; Moradi, Mehri & Sendtner, Michael
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Calnexin controls TrkB cell surface transport and ER-phagy in mouse cerebral cortex development. Developmental Cell, 58(18), 1733-1747.e6.
Lüningschrör, Patrick; Andreska, Thomas; Veh, Alexander; Wolf, Daniel; Giridhar, Neha Jadhav; Moradi, Mehri; Denzel, Angela & Sendtner, Michael
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Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy. Journal of Cell Biology, 222(3).
Hennlein, Luisa; Ghanawi, Hanaa; Gerstner, Florian; Palominos, García Eduardo; Yildirim, Ezgi; Saal-Bauernschubert, Lena; Moradi, Mehri; Deng, Chunchu; Klein, Teresa; Appenzeller, Silke; Sauer, Markus; Briese, Michael; Simon, Christian; Sendtner, Michael & Jablonka, Sibylle
