Atlastin-1 regulates morphology and function of endoplasmic reticulum in dendrites

Abstract

Endoplasmic reticulum (ER) is characterized by interconnected tubules and sheets. Neuronal ER adopts specific morphology in axons, dendrites and soma. Here we study mechanisms underlying ER morphogenesis in a C. elegans sensory neuron PVD. In PVD soma and dendrite branch points, ER tubules connect to form networks. ER tubules fill primary dendrites but only extend to some but not all dendritic branches. We find that the Atlastin-1 ortholog, atln-1 is required for neuronal ER morphology. In atln-1 mutants with impaired GTPase activity, ER networks in soma and dendrite branch points are reduced and replaced by tubules, and ER tubules retracted from high-order dendritic branches, causing destabilized microtubule in these branches. The abnormal ER morphology likely causes defects in mitochondria fission at dendritic branch points. Mutant alleles of Atlastin-1 found in Hereditary Spastic Paraplegia (HSP) patients show similar ER phenotypes, suggesting that neuronal ER impairment contributes to HSP disease pathogenesis.

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

“…As in yeast and mammalian cell culture models (Hu et al, 2009;Kornak et al, 2014;Wang S. et al, 2016), depletion of ATL in Drosophila neurons leads to tubular ER fragmentation and unbranched ER tubules (Orso et al, 2009). Similar branching defects have also been reported in C. elegans neurons mutated in atln-1, the ATL1 ortholog (Liu et al, 2019). In addition to their GTPase catalytic domain, ATLs also possess intramembrane domains, similar to those found in RTNs and REEPs, that are not only essential for ATL membrane fusion activity, but also could explain why ATL1 drives the generation of membrane tubules from proteoliposomes in vitro (Betancourt-Solis et al, 2018).…”

Loss of the Mitochondrial Fission GTPase Drp1 Contributes to Neurodegeneration in a Drosophila Model of Hereditary Spastic Paraplegia

“…Given the important role of the ER in the regulation of mitochondrial fission, it has been hypothesised that dysregulation of this process may contribute to neurodegeneration in HSP. Animal models of HSP generated by loss of the ER-shaping proteins Atlastin, Reticulon or ARL6IP1 result in mitochondrial elongation and defective mitochondrial fission in neurons [19,20]. Fibroblasts from HSP patients with mutations in the ER-shaping protein REEP1 also display elongated mitochondria and hyperphosphorylated Drp1 compared to healthy controls which can be rescued by overexpression of Drp1 or inhibiting Drp1 S637 phosphorylation [21].…”

Homeostatic Roles of the Proteostasis Network in Dendrites

“…This specialized neuronal secretory system is necessary for neuronal polarization and the asymmetric growth and branching that distinguishes axons from dendrites (Horton and Ehlers, 2003;Horton et al, 2005;Ye et al, 2007). The ER runs in a "tubular" form in axons and the straightaways of dendrites but creates more complicated satellite networks at dendritic branch points (Liu et al, 2019). Proper ER formation may underlie correct dendritic arbor formation (Cui-Wang et al, 2012).…”

“…These results are similar to those of experiments manipulating the protein Atlastin -an ER tubule-binding protein which, when mutated is a cause of Hereditary Spastic Paraplegia, discussed in sections "Protein Synthesis Linked to Neurological Disease" and "Protein Maintenance in Disease" (Fink, 2013;Ozdowski et al, 2015). In Drosophila, knockdown of atlastin orthologs leads to ER network fragmentation in dendrites, though dendritic arborization defects only resulted when the knockdown was combined with a knockdown of inositol-requiring enzyme-1 (IRE1) (see section "Protein Synthesis Linked to Neurological Disease") (Liu et al, 2019;Summerville et al, 2016). Furthermore, overexpression of Atlastin in mouse cortical neurons led to increased dendritic growth both in vivo and in vitro (Gao et al, 2013).…”

“…The neurological disease is thought to stem mainly from axon degeneration, and disruptions in axonal regeneration and bouton number have been reported with mutations in Hereditary Spastic Paraplegia-associated genes (Rao et al, 2016;Summerville et al, 2016). However, loss-of-function experiments with atlastin and other molecules have also been found to severely disrupt gross dendritic morphology and dendritic spine formation (Fink, 2013;Liu et al, 2019;Shih and Hsueh, 2018). Moreover, mutations in spastin, which encodes a microtubule-severing AAA ATPase, are known to be the most frequent cause of autosomal dominant spastic paraplegia, and have also been shown to lead to reductions in dendritic arbor complexity (Jinushi-Nakao et al, 2007;Ye et al, 2011).…”