Lipids in neuronal physiology and pathology

Research summary:

Our laboratory is interested in understanding the role of lipids in neuronal physiology and pathology focusing on their participation in synapses. In recent years our knowledge about the protein machinery that controls synaptic transmission has greatly increased. However, much less is known about the contribution of lipids to this process despite the fact that binding to the membrane, of which lipids are major components, modulates the activity of essential synaptic proteins. Moreover, synaptic transmission relies on membrane dynamics. The observation that most lipidosis lead to cognitive impairment and mental retardation further support the relevance of lipids in such process. We focus on the analysis of sphingolipids and cholesterol because, among other reasons, they are particularly enriched in neurons and have the ability to form signalling platforms. As experimental models we use mice in which enzymes related to lipid metabolism or lipid transport proteins have been genetically altered allowing in vivo analysis. These mice mimic fatal lysosomal storage disorders, such as Niemann pick type A and C, which lead to cognitive and psychiatric problems, neurodegeneration and early death. Interestingly, the lipidic alterations we have found in these mice are similar to those reported in aging brains. This opens the possibility that our results will have implications not only in the establishment and maintenance of synapses but also in their functional decay during aging. Therefore, we hope our work will contribute to understand and treat neurological diseases in childhood as well as neurodegenerative disorders like Alzheimer's disease.

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Figure 1: The figure exemplifies the drastic effects that changes in sphingolipid levels have in synapses. Electron microscopy analysis in the hippocampus of age-matched wild type and acid sphingomyelinase knockout mice evidence a significant size reduction of the pre and postsynaptic compartments in the mutant animals, which show high levels of sphingomyelin and its derivatives.

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Last nameNameLaboratoryExt.*e-mailProfessional category
Gaudioso GuiradoÁngel2024597angel.gaudioso(at)cbm.csic.esInvestigador
Guerrero ValeroMarta2024535mguerrero(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Ledesma MuñozMaría Dolores2024535dledesma(at)cbm.csic.esE.Científicos Titulares de Organismos Públicos de Investigación
Mulero FrancoJaime2024535Estudiante TFG
Naya ForcanoSara2024597snaya(at)cbm.csic.esAyudante Investigación
Soto HuelinBeatriz2024597beatriz.soto(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Toledano ZaragozaAna2024597atoledano(at)cbm.csic.esTit.Sup.Activ.Técn.y Profes. GP1 66%

Relevant publications:

  • M.D. Ledesma, M.G. Martin, C.G. Dotti. Lipid changes in the aged brain: effect on synaptic function and neuronal survival. (2012) Prog. Lipid Res. 51: 23-35.
  • A.I. Arroyo, P.G. Camoletto, L. Morando, M. Sassoe-Pognetto, M. Giustetto, P.P. Van Veldhoven, E.H. Schuchman, M.D. Ledesma “Pharmacological reversion of sphingomyelin-induced dendritic spine anomalies in a mouse model for Niemann Pick disease type A”. (2014) EMBO Mol Med 6(3):398-413.
  • E. Gabandé-Rodriguez, P. Boya, V. Labrador, C.G. Dotti, M.D. Ledesma. High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A. (2014) Cell Death & Diff. 21:864-875.
  •  A. Franco-Villanueva, E. Fernández-López, E. Gabandé-Rodríguez, I. Bañón-Rodríguez, J.A. Esteban, I.M. Antón, M.D. Ledesma. WIP modulates dendritic spine actin cytoskeleton by transcriptional control of lipid metabolic enzymes. (2014) Hum. Mol. Genet. 15:4383-4395.
  • A. Pérez-Cañamás, S. Sarroca, C. Melero-Jerez, D. Porquet, J. Sansa, S. Knafo, J.A. Esteban, C. Sanfeliu, M.D. Ledesma. Neurobiol Aging. (2016) 48:1-12.
  • A.Pérez-Cañamás, S. Benvegnù, C.B. Rueda, A. Rábano, J. Satrústegui, M.D. Ledesma.Sphingomyelin-induced inhibition of the plasma membrane calcium ATPase causes neurodegeneration in type A Niemann-Pick disease. Mol Psychiatry. (2017) 22: 711-723.
  • Gabandé-Rodríguez E, Pérez-Cañamás A, Soto-Huelin B, Mitroi DN, Sánchez-Redondo S, Martínez-Sáez E, Venero C, Peinado H, Ledesma MD.Lipid-induced lysosomal damage after demyelination corrupts microglia protective function in lysosomal storage disorders. EMBO J. (2019) 38 (2): 1-22.
  • L.Samaranch, A. Pérez-Cañamás, B. Soto-Huelin, V. Sudhakar, J. Jourado-Arjona, P. Hadaczek, J. Ávila, J.R. Bringas, J. Casas, H. Chen, X.He, E.H. Schuchman, S.H. Cheng, J. Forsayeth, K.S. Bankiewicz, M.D. Ledesma. Adeno-associated viral vector serotype 9-based gene therapy for Niemann Pick disease type A. Science Transl Med. (2019) 11 (506).
  • D.N. Mitroi, G. Pereyra-Gómez, B. Soto-Huelin, F. Senovilla, T. Kobayashi, J.A. Esteban, M.D. Ledesma. NPC1 enables cholesterol mobilization during long-term potentiation that can be restored in Niemann-Pick disease type C by CYP46A1 activation. EMBO Rep. (2019) e48143.

Doctoral theses:

  • Estefanía Fernández López. “Influencia de WIP en el citoesqueleto de actina y la composición lipídica de las espinas dendríticas”, Junio 2013, Universidad Autónoma Madrid. Sobresaliente Cum laude. Directores: María Dolores Ledesma, Inés Antón.
  • Enrique Gabandé Rodríguez. “Alteraciones de la autofagia mediadas por la acumulación de esfingomielina en la enfermedad de Niemann Pick tipo A”, Julio 2014 Universidad Autónoma Madrid. Sobresaliente Cum laude. Directores: María Dolores Ledesma, Carlos Dotti.
  • Cristian Galván. “Relevancia de los rafts en la polaridad neuronal e implicancias de sus alteraciones en la enfermedad de Niemann Pick tipo A”, Agosto 2014 Universidad Católica de Córdoba, Argentina. Sobresaliente Cum laude. Directores: María Dolores Ledesma, Dante Beltramo.
  • Ana Isabel Arroyo Tejedor. “Caracterización y rescate de las anomalías en espinas dendríticas en un modelo murino para la enfermedad de Niemann Pick tipo A”, Octubre 2014  Universidad Autónoma Madrid. Sobresaliente Cum laude. Directora: María Dolores Ledesma.
  • Azucena Pérez Cañamás. “Alteraciones de la homeostasis de calcio y esters oxidativo en neuronas deficientes en la esfingomielinasa ácida. Implicaciones en la enfermedad de Niemann Pick tipo A. Junio 2015 Universidad Autónoma Madrid. Sobresaliente Cum laude. Directora: María Dolores Ledesma.
  • Adrián Bartoll Andrés. “El sistema endocannabinoide en la patología y terapia de la enfermedad de Niemann Pick tipo A”, Mayo 2019, Universidad Autónoma Madrid. Sobresaliente Cum laude. Directora: María Dolores Ledesma.

Patents:

  • Methods and compositions for treatment of Alzheimer’s disease by enhancing plasmin or plasmin-like activity”. Inventores: M.D.Ledesma, C.G.Dotti. No. 09/502,448/ 2000, Julio 2000.
  • Method for the treatment of Niemann Pick disease type A and related neurological disorders through the activation of neutral sphingomyelinase. Inventores: A.I. Arroyo, P.G. Camoletto, M.D. Ledesma. Oficina española de patentes No. P201131297, Julio 2011.
  • Compositions and methods for activating signaling through the CB1 cannabinoid receptor for treating and preventing diseases and disorders characterized by abnormal celular accumulation of sphingolipids such as sphingomyelin. Inventores: M.D. Ledesma, A. Bartoll, E.H.Schuchman. US patent office Application number: 62638837, Marzo 2018.
  • Use of Efavirenz for the treatment of Lipid Storage Diseases. Inventores: D.N. Mitroi, M.D. Ledesma. Oficina española de patentes No: P201830486, Mayo 2018.

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