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Lipids and synaptic functions

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Journal of Inherited Metabolic Disease

Abstract

Synaptic functions have long been thought to be driven by proteins, especially the SNARE complex, contrasting with a relatively passive role for lipids constituting cell membranes. It is now clear that not only lipids, i.e. glycerophospholipids, sphingolipids and sterols, play a determinant role in the dynamics of synaptic membranes but they also actively contribute to the endocytosis and exocytosis of synaptic vesicles in conjunction with synaptic proteins. On the other hand, a growing number of inborn errors of metabolism affecting the nervous system have been related to defects in the synthesis and remodelling of fatty acids, phospholipids and sphingolipids. Alterations of the metabolism of these lipids would be expected to affect the dynamics of synaptic membranes and synaptic vesicles. Still, only few examples are currently documented. It remains to be determined to which extent the pathophysiology of disorders of complex lipids biosynthesis and remodelling share common pathogenic mechanisms with the more traditional synaptopathies.

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References

  • Boukhris A, Schule R, Loureiro JL et al (2013) Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. Am J Hum Genet 93:118–123

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bruckner RJ, Mansy SS, Ricardo A et al (2009) Flip-flop-induced relaxation of bending energy: implications for membrane remodeling. Biophys J 97:3113–3122

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cortès-Saladelafont E, Tristán-Noguero A, Artuch R et al (2016) Diseases of the synaptic vesicle: a potential new group of neurometabolic disorders affecting neurotransmission. Semin Pediatr Neurol 23:306–320

    Article  PubMed  Google Scholar 

  • Darios F, Connell E, Davletov B (2007) Phospholipases and fatty acid signalling in exocytosis. J Physiol 585:699–704

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Darios F, Wasser C, Shakirzyanova A et al (2009) Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis. Neuron 62:683–694

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657

    Article  CAS  PubMed  Google Scholar 

  • Fahy E, Subramaniam S, Brown HA et al (2005) A comprehensive classification of lipids. J Lipid Res 46:839–861

    Article  CAS  PubMed  Google Scholar 

  • Fiskerstrand T, H'mida-Ben Brahim D, Johansson S et al (2010) Mutations in ABHD12 cause the neurodegenerative disease PHARC: an inborn error of endocannabinoid metabolism. Am J Hum Genet 87:410–417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Garcia-Cazorla À, Mochel F, Lamari F et al (2015) The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview. J Inherit Metab Dis 38:19–40

    Article  CAS  PubMed  Google Scholar 

  • Hammer MB, Eleuch-Fayache G, Schottlaender LV et al (2013) Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet 92:245–251

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hammond GR, Balla T (2015) Polyphosphoinositide binding domains: key to inositol lipid biology. Biochim Biophys Acta 1851:746–758

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hoover-Fong J, Sobreira N, Jurgens J et al (2014) Mutations in PCYT1A, encoding a key regulator of phosphatidylcholine metabolism, cause spondylometaphyseal dysplasia with cone-rod dystrophy. Am J Hum Genet 94:105–112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Illingworth MA, Meyer E, Chong WK et al (2014) PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. Mol Genet Metab 112:183–189

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Klouwer FCC, Ferdinandusse S, van Lenthe H et al (2017) Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders. J Inherit Metab Dis 40:875–881

    Article  CAS  PubMed  Google Scholar 

  • Krebs CE, Karkheiran S, Powell JC et al (2013) The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures. Hum Mutat 34:1200–1207

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kruer MC, Paisán-Ruiz C, Boddaert N et al (2010) Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann Neurol 68:611–618

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lamari F, Mochel F, Sedel F et al (2013) Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases. J Inherit Metab Dis 36:411–425

    Article  CAS  PubMed  Google Scholar 

  • Lamari F, Mochel F, Saudubray JM (2015) An overview of inborn errors of complex lipid biosynthesis and remodelling. J Inherit Metab Dis 38:3–18

    Article  CAS  PubMed  Google Scholar 

  • Lang T, Bruns D, Wenzel D et al (2001) SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J 20:2202–2213

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lauwers E, Goodchild R, Verstreken P (2016) Membrane lipids in presynaptic function and disease. Neuron 90:11–25

    Article  CAS  PubMed  Google Scholar 

  • Lefèvre C, Jobard F, Caux F et al (2001) Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome. Am J Hum Genet 69:1002–1012

    Article  PubMed Central  PubMed  Google Scholar 

  • Martin E, Schüle R, Smets K et al (2013) Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet 92:238–244

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mitsuhashi S, Ohkuma A, Talim B et al (2011) A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis. Am J Hum Genet 88:845–851

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mitter D, Reisinger C, Hinz B et al (2003) The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content. J Neurochem 84:35–42

    Article  CAS  PubMed  Google Scholar 

  • Mosbech MB, Olsen AS, Neess D et al (2014) Reduced ceramide synthase 2 activity causes progressive myoclonic epilepsy. Ann Clin Transl Neurol. 1: 88–98

  • Narkis G, Ofir R, Landau D et al (2007a) Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway. Am J Hum Genet 81:530–539

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Narkis G, Ofir R, Manor E et al (2007b) Lethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/Akt pathway. Am J Hum Genet 81:589–595

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Nishiguchi KM, Avila-Fernandez A, van Huet RA et al (2014) Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration. Ophthalmology 121:1620–1627

    Article  PubMed  Google Scholar 

  • Paisan-Ruiz C, Bhatia KP, Li A et al (2009) Characterization of PLA2G6 as a locus for dystonia-parkinsonism. Ann Neurol 65:19–23

    Article  PubMed  PubMed Central  Google Scholar 

  • Pettazzoni M, Froissart R, Pagan C et al (2017) LC-MS/MS multiplex analysis of lysosphingolipids in plasma and amniotic fluid: a novel tool for the screening of sphingolipidoses and Niemann-Pick type C disease. PLoS One 12:e0181700

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Piomelli D, Astarita G, Rapaka R (2007) A neuroscientist’s guide to lipidomics. Nat Rev Neurosci 8:743–754

    Article  CAS  PubMed  Google Scholar 

  • Rohrbough J, Broadie K (2005) Lipid regulation of the synaptic vesicle cycle. Nat Rev Neurosci 6:139–150

    Article  CAS  PubMed  Google Scholar 

  • Rotthier A, Auer-Grumbach M, Janssens K et al (2010) Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I. Am J Hum Genet 87:513–522

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schuurs-Hoeijmakers JH, Geraghty MT, Kamsteeg EJ et al (2012) Mutations in DDHD2, encoding an intracellular phospholipase A(1), cause a recessive form of complex hereditary spastic paraplegia. Am J Hum Genet 91:1073–1081

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Seyer A, Boudah S, Broudin S et al (2016) Annotation of the human cerebrospinal fluid lipidome using high resolution mass spectrometry and a dedicated data processing workflow. Metabolomics 12:91–104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Simpson MA, Cross H, Proukakis C et al (2004) Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase. Nat Genet 36:1225–1229

    Article  CAS  PubMed  Google Scholar 

  • Sousa SB, Jenkins D, Chanudet E et al (2014) Gain-of-function mutations in the phosphatidylserine synthase 1 (PTDSS1) gene cause Lenz-Majewski syndrome. Nat Genet 46:70–76

    Article  CAS  PubMed  Google Scholar 

  • Sumi-Akamaru H, Beck G, Kato S et al (2015) Neuroaxonal dystrophy in PLA2G6 knockout mice. Neuropathology 35:289–302

    Article  CAS  PubMed  Google Scholar 

  • Synofzik M, Gonzalez MA, Lourenco CM et al (2014) PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. Brain 137:69–77

    Article  PubMed  Google Scholar 

  • Tesson C, Nawara M, Salih MA et al (2012) Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. Am J Hum Genet 91:1051–1064

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thiele C, Hannah MJ, Fahrenholz F et al (2000) Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles. Nat Cell Biol 2:42–49

    Article  CAS  PubMed  Google Scholar 

  • Tu-Sekine B, Goldschmidt H, Raben DM (2015) Diacylglycerol, phosphatidic acid, and their metabolic enzymes in synaptic vesicle recycling. Adv Biol Regul 57:147–152

    Article  CAS  PubMed  Google Scholar 

  • Ueda Y (2014) The role of phosphoinositides in synapse function. Mol Neurobiol 50:821–838

    Article  CAS  PubMed  Google Scholar 

  • Wierda KD, Toonen RF, de Wit H et al (2007) Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity. Neuron 54:275–290

    Article  CAS  PubMed  Google Scholar 

  • Williams D, Vicôgne J, Zaitseva I et al (2009) Evidence that electrostatic interactions between vesicle-associated membrane protein 2 and acidic phospholipids may modulate the fusion of transport vesicles with the plasma membrane. Mol Biol Cell 20:4910–4919

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wortmann SB, Vaz FM, Gardeitchik T et al (2012) Mutations in the phospholipid remodeling gene SERAC1 impair mitochondrial function and intracellular cholesterol trafficking and cause dystonia and deafness. Nat Genet 44:797–802

    Article  CAS  PubMed  Google Scholar 

  • Zeharia A, Shaag A, Houtkooper RH et al (2008) Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood. Am J Hum Genet 83:489–494

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgements

The author is very grateful to Pr Jean-Marie Saudubray and Dr. Foudil Lamari for their pioneering and invaluable contribution to the delineation of the novel class of inborn errors of metabolism represented by disorders of complex lipids biosynthesis and remodelling.

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Authors and Affiliations

  1. Sorbonne Université, UPMC-Paris 6, UMR S 1127 and Inserm U 1127, and CNRS UMR 7225, and ICM, F-75013, Paris, France

    Fanny Mochel

  2. Sorbonne Université, GRC no. 13, Neurométabolisme, Paris, France

    Fanny Mochel

  3. Department of Genetics and Reference Centre for Adult Neurometabolic Diseases, AP-HP, La Pitié-Salpêtriere University Hospital, Paris, France

    Fanny Mochel

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  1. Fanny Mochel
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Correspondence to Fanny Mochel.

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Fanny Mochel declares that she has no conflict of interest.

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Communicated by: Sander M Houten

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Mochel, F. Lipids and synaptic functions. J Inherit Metab Dis 41, 1117–1122 (2018). https://doi.org/10.1007/s10545-018-0204-1

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  • DOI: https://doi.org/10.1007/s10545-018-0204-1

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