Abstract
The endoplasmic reticulum (ER) extends as a network of interconnected tubules and sheet-like structures in eukaryotic cells. ER tubules dynamically change their morphology and position within the cells in response to physiological stimuli and these network rearrangements depend on the microtubule (MT) cytoskeleton. Store-operated calcium entry (SOCE) relies on the repositioning of ER tubules to form specific ER-plasma membrane junctions. Indeed, the tips of polymerizing MTs are supposed to provide the anchor for ER tubules to move toward the plasma membrane, however the precise role of the cytoskeleton during SOCE has not been conclusively clarified. Here we exploit an in vivo approach involving the manipulation of MT dynamics in Drosophila melanogaster by neuronal expression of a dominant-negative variant of the MT-severing protein spastin to induce MT hyper-stabilization. We show that MT stabilization alters ER morphology, favoring an enrichment in ER sheets at the expense of tubules. Stabilizing MTs has a negative impact on the process of SOCE and results in a reduced ER Ca2+ content, affecting the flight ability of the flies. Restoring proper MT organization by administering the MT-destabilizing drug vinblastine, chronically or acutely, rescues ER morphology, SOCE and flight ability, indicating that MT dynamics impairment is responsible for all the phenotypes observed.
Highlights
The endoplasmic reticulum (ER) coordinates a variety of cellular processes, such as synthesis, modification, quality control and transport of proteins, as well as lipid metabolism and Ca2+ homeostasis
Increasing evidence suggests that neurons rely on Store-operated calcium entry (SOCE) and its dysregulation may participate in the pathogenesis of diverse neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Charcot-Marie-Tooth (Secondo et al, 2018)
The aim of this study was to determine the influence of neuronal MT cytoskeleton architecture on the process of SOCE, the opening of plasma membrane (PM) Ca2+ channels that follows the release of Ca2+ from intracellular stores
Summary
The endoplasmic reticulum (ER) coordinates a variety of cellular processes, such as synthesis, modification, quality control and transport of proteins, as well as lipid metabolism and Ca2+ homeostasis. A part of the neuronal MTs is Spastin-Mediated Microtubules Stabilization Impairs SOCE considered stable, a fraction retains high levels of dynamics, as demonstrated by their frequent and continuous growth and shortening (Desai and Mitchison, 1997; Nogales, 2001; Burbank and Mitchison, 2006). This dynamic instability is central to MT biological functions, allowing their rapid reorganization at need (Kirschner and Mitchison, 1986). Dysfunctional MTs, due to mutations in genes that encode tubulin or MT-associated proteins, have been linked to a range of neuronal diseases, such as motor neuropathies, Hereditary Spastic Paraplegias (HSPs), Charcot–Marie–Tooth disease
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