Saturday, 23rd June 2018

Molecular Neuropathology

    Role of Lipids in Neuronal Physiology and Pathology







María Dolores Ledesma










Research summary: 



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.

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 in 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 have been genetically altered allowing in vivo analysis. At present we study mice deficient in the acid sphingomyelinase and in seladin1, which participate in sphingomyelin turnover and cholesterol synthesis, respectively. These mice mimic human genetic diseases, such as Niemann pick type A and desmosterolosis, which cause severe mental retardation. Interestingly, the lipidic alterations we have found in these mice (Crameri et al., EMBO J, 2006; Galvan et al., Mol. Biol. Cell, 2008) 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 neurological diseases in childhood as well as neurodegenerative disorders like Alzheimer's disease.



Relevant publications:

A. Crameri, E. Biondi, K. Kuehnle, D. Lütjohann, K.M. Thelen, S. Perga,C.G. Dotti, R. M. Nitsch, M.D. Ledesma*, M. H. Mohajeri*.“Seladin-1/DHCR24 role in cholesterol biosynthesis, APP processing and Abgeneration in vivo”. (2006) EMBO J. 25:432-443. *corresponding authors

C. Galvan, P.G. Camoletto, F. Cristofani, P.P. Van Veldhoven, M.D Ledesma. “Anomalous surface distribution of GPI-anchored proteins in neurons lacking acid sphingomyelinase”. (2008) Mol. Biol. Cell. 19: 509-522.

P.G.Camoletto, H.Vara, L.Morando, E.Connell, F.P. Marletto, M.Giustetto, M.Sassoé-Pognetto, P.P.Van Veldhoven, M.D. Ledesma. "Synaptic vesicle docking: sphingosine regulates syntaxin1 interaction with Munc18" (2009) PLoS One 4(4): e5310.

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.




Doctoral Theses:

Cristian Galván. “Participación de la esfingomielina y el colesterol en el establecimiento de la polaridad neuronal. Implicaciones en la enfermedad de Niemann Pick tipo A”. Universidad Nacional de Córdoba, Argentina. 2008.

Estefanía Fernández López. "Influencia de WIP en el citoesqueleto de actina y la composición lipídica de las espinas dendríticas". Universidad Autónoma Madrid. June 2013

Enrique Gabandé Rodríguez. "Alteraciones de la autofagia mediadas por la acumulación de esfingomielina en la enfermedad de Niemann Pick tipo A". Universidad Autónoma Madrid. July 2014




M.D.Ledesma, C.G.Dotti. Methods and compositions for treatment of Alzheimer’s disease by enhancing plasmin or plasmin-like activity”. No. 09/502,448/ 2000

A.I. Arroyo, P.G. Camoletto, M.D. Ledesma. Method for the treatment of Niemann Pick disease type A and related neurological disorders through the activation of neutral sphingomyelinase. Application number P201131297/  July 2011