Impaired dynamic interaction of axonal endoplasmic reticulum and ribosomes contributes to defective stimulus-response in spinal muscular atrophy  

作　　者：Chunchu Deng Sebastian Reinhard Luisa Hennlein Janna Eilts Stefan Sachs Sören Doose Sibylle Jablonka Markus Sauer Mehri Moradi Michael Sendtner 

机构地区：[1]Institute of Clinical Neurobiology,University Hospital Wuerzburg,97078 Wür-zburg,Germany [2]Department of Biotechnology and Biophysics,Biocenter,Julius-Maximilians-University Wuerzburg,97074 Würzburg,Germany.

出　　处：《Translational Neurodegeneration》2022年第1期474-495,共22页转化神经变性病（英文）

基　　金：Open Access funding enabled and organized by Projekt DEAL.Chunchu Deng was funded by PicoQuant and the Deutsche Forschungsgemeinschaft(DFG)Grant Se697/7-1,Project Number 405988308,DFG Grant JA1823/3-1 for SJ and Cure SMA for SJ,Grant JAB1920.PicoQuant did not influence project design,conduction of experiments or data analyses.

摘　　要：Background:Axonal degeneration and defects in neuromuscular neurotransmission represent a pathological hall-mark in spinal muscular atrophy(SMA)and other forms of motoneuron disease.These pathological changes do not only base on altered axonal and presynaptic architecture,but also on alterations in dynamic movements of organelles and subcellular structures that are not necessarily reflected by static histopathological changes.The dynamic inter-play between the axonal endoplasmic reticulum(ER)and ribosomes is essential for stimulus-induced local translation in motor axons and presynaptic terminals.However,it remains enigmatic whether the ER and ribosome crosstalk is impaired in the presynaptic compartment of motoneurons with Smn(survival of motor neuron)deficiency that could contribute to axonopathy and presynaptic dysfunction in SMA.Methods:Using super-resolution microscopy,proximity ligation assay(PLA)and live imaging of cultured motoneu-rons from a mouse model of SMA,we investigated the dynamics of the axonal ER and ribosome distribution and activation.Results:We observed that the dynamic remodeling of ER was impaired in axon terminals of Smn-deficient motoneu-rons.In addition,in axon terminals of Smn-deficient motoneurons,ribosomes failed to respond to the brain-derived neurotrophic factor stimulation,and did not undergo rapid association with the axonal ER in response to extracellular stimuli.Conclusions:These findings implicate impaired dynamic interplay between the ribosomes and ER in axon terminals of motoneurons as a contributor to the pathophysiology of SMA and possibly also other motoneuron diseases.

关 键 词：Spinal muscular atrophy Presynaptic ER dynamics Dynamics of ribosomal assembly BDNF stimulation 

分 类 号：R746.4[医药卫生—神经病学与精神病学]