Spastin mutations impair coordination between lipid droplet dispersion and reticulum

Lipid droplets (LD) are affected in multiple human disorders.These highly dynamic organelles are involved in many cellular roles.While their intracellular dispersion is crucial to ensure their function and other organelles-contact, underlying mechanisms are still unclear.Here we show that Spastin, one of the major proteins involved in Hereditary Spastic Paraplegia (HSP), controls LD dispersion.Spastin depletion in zebrafish affects metabolic properties and organelle dynamics.These functions are ensured by a conserved complex set of splice variants.M1 isoforms determine LD dispersion in the cell by orchestrating endoplasmic reticulum (ER) shape along microtubules (MTs).To further impact LD fate, Spastin modulates transcripts levels and subcellular location of other HSP key players, notably Seipin and REEP1.In pathological conditions, mutations in human Spastin M1 disrupt this mechanism and impacts LD network.Spastin depletion influences not only other key proteins but also modulates specific neutral lipids and phospholipids, revealing an impact on membrane and organelle components.Altogether our results show that Spastin and its partners converge in a common machinery that coordinates LD dispersion and ER shape along MTs.Any alteration of this system results in HSP clinical features and impacts lipids profile, thus opening new avenues for novel biomarkers of HSP. Author summaryHereditary spastic paraplegia is a group of inherited diseases characterized by spasticity and gait disorder.Spastin mutations represent the most common cause of hereditary spastic paraplegia.While Spastin was initially defined as a microtubule severing protein, alternative isoforms impact organelles.In the present work, we identify how Spastin combines the specificity of different splice variants to coordinate endoplasmic reticulum shape and lipid droplet dispersion.When mutated, Spastin impairs this synchronization between organelle dynamics, and affects other proteins involved in hereditary spastic paraplegia,