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.

脂滴（LD）在多种人类疾病中受到影响。这些高度动态的细胞器在众多细胞功能中扮演重要角色。尽管其细胞内分散对于确保其功能及其他细胞器接触至关重要，但其潜在的机制尚不明确。本研究揭示，Spastin蛋白，作为遗传性痉挛性截瘫（HSP）的主要蛋白之一，控制着脂滴的分散。zebrafish中Spastin的减少影响了代谢特性及细胞器动力学。这些功能通过保守的剪接变异体复合体得以保证。M1型异构体通过调节沿微管（MTs）的内质网（ER）形状来决定细胞内脂滴的分散。为了进一步影响脂滴的命运，Spastin通过调节其他HSP关键因子，特别是Seipin和REEP1的转录水平和亚细胞定位来发挥作用。在病理条件下，人类Spastin M1中的突变破坏了这一机制，并影响了脂滴网络。Spastin的减少不仅影响了其他关键蛋白，还调节了特定的中性脂和磷脂，揭示了其对膜和细胞器成分的影响。总之，我们的研究结果表明，Spastin及其合作伙伴汇聚于一个共同的机制中，该机制协调脂滴的分散和沿微管的内质网形状。任何对该系统的改变都将导致HSP的临床特征，并影响脂质谱，从而为HSP的新型生物标志物开辟了新的途径。