Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

Abstract

Abstract:Axons contain an endoplasmic reticulum (ER) network that is largely smooth and tubular, thought to be continuous with ER throughout the neuron, and distinct in form and function from rough ER; the mechanisms that form this continuous network in axons are not well understood. Mutations affecting proteins of the reticulon or REEP families, which contain intramembrane hairpin domains that can model ER membranes, cause an axon degenerative disease, hereditary spastic paraplegia (HSP). Here, we show that these proteins are required for modeling the axonal ER network in Drosophila. Loss of reticulon or REEP proteins can lead to expansion of ER sheets, and to partial loss of ER from distal motor axons. Ultrastructural analysis reveals an extensive ER network in every axon of peripheral nerves, which is reduced in larvae that lack reticulon and REEP proteins, with defects including larger and fewer tubules, and occasional gaps in the ER network, consistent with loss of membrane curvature.Therefore HSP hairpin-containing proteins are required for shaping and continuity of the axonal ER network, suggesting an important role for ER modeling in axon maintenance and function.

The axonal endoplasmic reticulum: One organelle—many functions in development, maintenance, and plasticity

“…How tubule stabilization affects the function of the axonal ER is still an open question. However, absence of reticulon 1 and both versions of REEP proteins (A and B) result in ER fragmentation on distal portions of motor axons in Drosophila (Yalçın et al, 2017). Additionally, downregulation or overexpression of Atlastin in motor neurons result in locomotor deficits in larvae and adult Drosophila, and correlate with defects in axonal secretory organelle and presynaptic protein distribution.…”

Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

“…For example, several mutations in hairpin-loop containing ER-shaping proteins such as reticulons, REEPs and atlastins have been described as causative of autosomal dominant hereditary spastic paraplegia (HSP), a condition where distal axons progressively degenerate resulting in severe motor and sensory symptoms [36,37]. Recent studies utilizing Drosophila models have shown that mutations in the reticulon and REEP families of ER-shaping proteins do indeed result in ER fragmentation and network disruption with physiological consequences in the distal axon, demonstrating that ER shaping and remodeling have direct effects on axon structure, function and maintenance [38,39,40].…”

Morphological Heterogeneity of the Endoplasmic Reticulum within Neurons and Its Implications in Neurodegeneration

“…Axonal ER is predominantly tubular, running parallel along the axonal length with intermittent small cisternae such as in the synaptic varicosities [ 23 ]. The larger axons have a network of interconnected tubules while a single axonal tubule is found in the thinner parts of the axon [ 23 , 161 , 162 , 163 ]. The ER tubules show extensive branching in the synaptic varicosities in the distal axon [ 23 ].…”

“…Using Automated Tape Collecting Ultramicrotomy (ATUM), a small but distinct population of very narrow ER tubules ranging between 20 and 30 nm in width were found in both central and peripheral system neurons [ 164 ]. These narrow tubules are particularly abundant in the axons, maintaining the ER density relatively constant along the axon length [ 23 , 163 , 164 ]. Regions of such ‘narrow constriction’ could have functional implications in the efficiency of transport of substances along the length of the tubule.…”