Dynamic remodeling of presynaptic endoplasmic reticulum is coordinated through actin and microtubule crosstalk and contributes to defective stimulus-response in Spinal Muscular Atrophy

Background Axonal degeneration and defects in neuromuscular neurotransmission represent a pathological hallmark 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. In neurons, a highly dynamic endoplasmic reticulum (ER) network exists in the axonal and presynaptic compartment which regulates Ca2+ homeostasis and synapse maintenance. However, the mechanisms of its dynamic regulation and mechanisms of dysfunction that contribute to neurodegeneration remain elusive. Methods Using high resolution microscopy and life imaging of cultured motoneurons from wildtype and a mouse model of spinal muscular atrophy, we investigated the dynamics of the axonal endoplasmic reticulum and ribosome distribution and activation. Results These studies revealed that the dynamic remodeling of ER in axonal filopodia of cultured motoneurons depends mainly on actin cytoskeleton. In Smn -deficient motoneurons, movements of ER in filopodia seems to be more affected than in the growth cone core. In addition, ribosome assembly that happens within seconds after exposure to Brain derived neurotrophic factors (BDNF) is reduced in axon terminals of Smn -deficient motoneurons, and also the association with ER as a response to extracellular stimuli is highly disturbed. Conclusions These findings do not only define a novel function of presynaptic ER in dynamic regulation of local translation. They also implicate impaired dynamic movements of axonal and presynaptic ER as a contributor to the pathophysiology of SMA and possibly also other neurodegenerative diseases.