Proteomics

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Inhibiting sphingolipid synthesis improves outcomes and survival in GARP-mutant wobbler mouse, an ALS model


ABSTRACT: Defects of the endosomal and lysosomal systems have been increasingly linked to adult neurodegenerative diseases1,2. Deficiencies in the retrograde trafficking pathway between endosomes and the Golgi apparatus lead to forms of Alzheimer’s and Parkinson’s diseases in the case of retromer mutations, or to the rare progressive cerebello-cerebral atrophy type 2 (PCCA2) for mutations of the Golgi-associated retrograde protein (GARP) complex3. Mutations in GARP subunits lead to abnormal cellular lipid metabolism, with accumulation of sterol esters and sphingoid bases, and concomitant lysosomal dysfunction in yeast, murine, or human cells4,5. However, whether these lipid changes cause neurodegeneration and if so, which lipids are toxic, is unknown. Here, we show that GARP defects lead to global changes of cellular protein distribution, including missorting of numerous disease-linked enzymes of sphingolipid metabolism, and to the accumulation of sphingolipid intermediates in wobbler fibroblasts. Inhibiting sphingolipid synthesis in wobbler mice, a murine model of GARP deficiency with features of amyotrophic lateral sclerosis (ALS), improved wellness scores and grip strength, and increased lifespan. Our findings indicate that regulation of sphingolipids by the GARP complex is essential for neuronal health and suggest that inhibition of sphingolipid synthesis might provide a therapeutic strategy for treatment of neurodegenerative diseases due to defects in retrograde endosome-to-Golgi membrane trafficking.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Fibroblast

SUBMITTER: Zon Weng Lai  

LAB HEAD: Tobias Walther

PROVIDER: PXD007981 | Pride | 2022-02-15

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
SILAC_MEF_replicate1_wobvswt.raw Raw
SILAC_MEF_replicate1_wobvswt.zip Other
SILAC_MEF_replicate2_wtvswob.raw Raw
SILAC_MEF_replicate2_wtvswob.zip Other
SILAC_MEF_replicate3_wobvswt.raw Raw
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Publications

Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant <i>wobbler</i> mice, a model of motor neuron degeneration.

Petit Constance S CS   Lee Jane J JJ   Boland Sebastian S   Swarup Sharan S   Christiano Romain R   Lai Zon Weng ZW   Mejhert Niklas N   Elliott Shane D SD   McFall David D   Haque Sara S   Huang Eric J EJ   Bronson Roderick T RT   Harper J Wade JW   Farese Robert V RV   Walther Tobias C TC  

Proceedings of the National Academy of Sciences of the United States of America 20200428 19


Numerous mutations that impair retrograde membrane trafficking between endosomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the endosomal retromer complex are implicated in Alzheimer's and Parkinson's diseases, and mutations of the Golgi-associated retrograde protein (GARP) complex cause progressive cerebello-cerebral atrophy type 2 (PCCA2). However, how these mutations cause neurodegeneration is unknown. GARP mutations in yeast, including one causing P  ...[more]

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