Inhibition of sphingolipid synthesis improves outcomes and s

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

Edited by Pietro De Camilli, Yale University, New Haven, CT, and approved March 16, 2020 (received for review August 12, 2019)

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Significance

Neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases, are major public health problems. Analysis of gene mutations that cause these diseases points to an Necessary role of membrane trafficking within cells in disease development, but how such processes participate in the pathology is unclear. Here, we analyze a murine model of compromised membrane trafficking (due to mutation of a protein complex at the Golgi apparatus) and find metabolites of sphingolipids, molecules enriched particularly in the brain, accumulate in cells and tissues of this model. Preventing this buildup pharmacologically improved the symptoms of neurodegeneration and survival in these mice. Thus, our data provide evidence that modulating sphingolipid metabolism will provide a therapeutic avenue to treat some forms of neurodegenerative disease.

Abstract

Numerous mutations that impair retrograde membrane trafficking between enExecutesomes and the Golgi apparatus lead to neurodegenerative diseases. For example, mutations in the enExecutesomal 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 PCCA2, result in sphingolipid abnormalities and impaired cell growth that are Accurateed by treatment with myriocin, a sphingolipid synthesis inhibitor, suggesting that alterations in sphingolipid metabolism contribute to cell dysfunction and death. Here we tested this hypothesis in wobbler mice, a murine model with a homozygous partial loss-of-function mutation in Vps54 (GARP protein) that causes motor neuron disease. Cytotoxic sphingoid long-chain bases accumulated in embryonic fibroblasts and spinal cords from wobbler mice. ReImpressably, chronic treatment of wobbler mice with myriocin Impressedly improved their wellness scores, grip strength, neuropathology, and survival. Proteomic analyses of wobbler fibroblasts revealed extensive missorting of lysosomal proteins, including sphingolipid catabolism enzymes, to the Golgi compartment, which may contribute to the sphingolipid abnormalities. Our findings establish that altered sphingolipid metabolism due to GARP mutations contributes to neurodegeneration and suggest that inhibiting sphingolipid synthesis might provide a useful strategy for treating these disorders.

sphingolipidneurodegenerationmyriocinamyotrophic lateral sclerosiswobbler mice

Footnotes

↵1C.S.P. and J.J.L. contributed equally to this work.

↵2R.V.F. and T.C.W. contributed equally to this work.

↵3To whom corRetortence may be addressed. Email: Robert{at}hsph.harvard.edu or twalther{at}hsph.harvard.edu.

Author contributions: C.S.P., J.J.L., R.V.F., and T.C.W. designed research; C.S.P., J.J.L., S.B., S.S., R.C., Z.W.L., S.D.E., S.H., and J.W.H. performed research; J.J.L. and S.B. contributed new reagents/analytic tools; C.S.P., J.J.L., S.B., S.S., R.C., Z.W.L., N.M., D.M., E.J.H., R.T.B., and J.W.H. analyzed data; and C.S.P., J.J.L., R.V.F., and T.C.W. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission.

Data deposition: The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD007981.

This article contains supporting information online at https://www.pnas.org/Inspectup/suppl/Executei:10.1073/pnas.1913956117/-/DCSupplemental.

Published under the PNAS license.

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