PXD007981

PXD007981 is an original dataset announced via ProteomeXchange.

Title	Inhibiting sphingolipid synthesis improves outcomes and survival in GARP-mutant wobbler mouse, an ALS model
Description	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.
HostingRepository	PRIDE
AnnounceDate	2022-02-15
AnnouncementXML	Submission_2022-02-15_08:46:14.883.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Zon Lai
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2017-10-17 06:04:20	ID requested
⏵ 1	2022-02-15 08:46:15	announced

Petit CS, Lee JJ, Boland S, Swarup S, Christiano R, Lai ZW, Mejhert N, Elliott SD, McFall D, Haque S, Huang EJ, Bronson RT, Harper JW, Farese RV, Walther TC, mice, a model of motor neuron degeneration. Proc Natl Acad Sci U S A, 117(19):10565-10574(2020) [pubmed]

curator keyword: Biomedical

submitter keyword: MEF, LC-MSMS, SILAC

Tobias Walther
contact affiliation	Harvard T. H. Chan School of Public Health
contact email	twalther@hsph.harvard.edu
lab head
Zon Lai
contact affiliation	Harvard T. H. Chan School of Public Health
contact email	zlai@hsph.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD007981
     1. Label: PRIDE project
     2. Name: Inhibiting sphingolipid synthesis improves outcomes and survival in GARP-mutant wobbler mouse, an ALS model