PUBLICATION

Spastin mutations impair coordination between lipid droplet dispersion and reticulum

Authors

Arribat, Y., Grepper, D., Lagarrigue, S., Qi, T., Cohen, S., Amati, F.

ID

ZDB-PUB-200422-174

Date

2020

Source

PLoS Genetics 16: e1008665 (Journal)

Registered Authors

Amati, Francesca, Arribat, Yoan, Grepper, Dogan, Lagarrigue, Silviane

Keywords

none

MeSH Terms

Cells, Cultured
GTP-Binding Protein gamma Subunits/metabolism
Animals
Humans
Membrane Transport Proteins/metabolism
Zebrafish
Endoplasmic Reticulum/metabolism*
Lipid Droplets/metabolism*
HeLa Cells
Protein Binding
Microtubules/metabolism
Spastin/genetics
Spastin/metabolism*

(all 13)

PubMed

32315314 Full text @ PLoS Genet.

Abstract

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.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
atl1	spast^ula1/ula1	standard conditions	Adult	brain	RTPCR	Fig 7
atl1	spast^ula1/ula1	standard conditions	Adult	skeletal muscle	RTPCR	Fig 7
atl1	WT	standard conditions	Adult	brain	RTPCR	Fig 7
atl1	WT	standard conditions	Adult	skeletal muscle	RTPCR	Fig 7
bscl2	spast^ula1/ula1	standard conditions	Adult	brain	RTPCR	Fig 7
bscl2	spast^ula1/ula1	standard conditions	Adult	skeletal muscle	RTPCR	Fig 7
bscl2	WT	standard conditions	Adult	brain	RTPCR	Fig 7
bscl2	WT	standard conditions	Adult	skeletal muscle	RTPCR	Fig 7
reep1	spast^ula1/ula1	standard conditions	Adult	brain	RTPCR	Fig 7
reep1	spast^ula1/ula1	standard conditions	Adult	skeletal muscle	RTPCR	Fig 7

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment by environment: oleic acid	Day 6	swimming increased occurrence, abnormal	Fig 3
spast^ula1/ula1	standard conditions	Long-pec	aerobic respiration decreased magnitude, abnormal	Fig 2
spast^ula1/ula1	standard conditions	Pec-fin	hatching delayed, abnormal	Fig 2
spast^ula1/ula1	standard conditions	Day 6	swim bladder anatomical region increased accumulation fat cell, abnormal	Fig 3
spast^ula1/ula1	standard conditions	Day 6	swimming occurrence, normal	Fig 3
spast^ula1/ula1	standard conditions	Adult	brain atl1 expression increased amount, abnormal	Fig 7
spast^ula1/ula1	standard conditions	Adult	brain reep1 expression increased amount, abnormal	Fig 7
spast^ula1/ula1	standard conditions	Adult	brain cholesterol normal amount, normal	Fig 8
spast^ula1/ula1	standard conditions	Adult	brain N-docosanoylsphingosine normal amount, normal	Fig 8
spast^ula1/ula1	standard conditions	Adult	brain N-hexacosanoylsphingosine normal amount, normal	Fig 8

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ula1		Small Deletion	spast

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
spast	CRISPR3-spast	CRISPR

Fish

Fish
spast^ula1/ula1
WT

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Arribat et al., 2020 ZDB-PUB-200422-174 PMID:32315314

Spastin mutations impair coordination between lipid droplet dispersion and reticulum

Arribat et al., 2020

ZDB-PUB-200422-174
PMID:32315314