The goal of the NeuroLipid Biology group is to understand how lipid synthesis and catabolism govern biological and functional processes in the healthy nervous tissue and in neurometabolic disorders. We are particularly interested in the role that ether-phospholipids play in neuron excitability, axon growth, and myelin synthesis. Using mouse models, we combine in vivo and in vitro studies to integrate physiological cell processes with disease states, and the development new therapeutic pre-clinical approaches.
The impact of lipid dysregulation in neurologic disorders is evident by the number and severity of neurometabolic diseases. However, we are limited in understanding the function of lipids and how fundamental cellular processes and mechanisms are affected by lipid dysregulation, and thus mediate tissue pathology and disease. Previous work highlighted the consequences of branched-chain fatty acid accumulation in ataxia, and we identified cholesterol and sphingomyelin as novel myelin-associated inhibitors that affect axon growth and regeneration.
Currently, our research is focused on the study of plasmalogens, a class of phospholipids highly enriched in nervous tissue, whose deficiency causes a rare peroxisomal disorder, rhizomelic chondrodysplasia punctata (RCDP). Previous work allowed us to unravel the genetic basis of RCDP and attain an understanding of the pathology through the usage of mouse models. In line with our goal of understanding the fundamental processes and mechanisms governed by plasmalogens, we unraveled that these lipids are crucial for Schwann cell differentiation and myelination, as plasmalogens are essential for the initiation of the signaling cascade mediated by activation at the plasma membrane of Protein kinase B, also known as AKT. Our aim is to expand the understanding of how fundamental cellular processes are governed by plasmalogens, and how a dysregulation of these processes mediates the pathophysiology of RCDP and other neurological disorders (e.g. Alzheimer's and Parkinson's) known to develop defects in plasmalogen levels. The knowledge gathered in understanding the mechanisms behind the pathology is also used to design and validate effective pre-clinical therapeutic strategies.
Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1-myristyl ether treatment. Brain Pathology29(5):622-639, 2019. [Journal: Article] [CI: 10] [IF: 5,6]
DOI: 10.1111/bpa.12710 SCOPUS: 85061900503. .
Da Silva T.F., Eira J., Lopes A.T., Malheiro A.R., Sousa V., Luoma A., Avila R.L., Wanders R.J.A., Just W.W., Kirschner D.A., Sousa M.M., Brites P.,
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination. Journal of Clinical Investigation124(6):2560-2570, 2014. [Journal: Article] [CI: 54] [IF: 13,2]
DOI: 10.1172/JCI72063 SCOPUS: 84902172153. .
Wanders R.J.A., Ferdinandusse S., Brites P., Kemp S.,
Peroxisomes, lipid metabolism and lipotoxicity. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids1801(3):272-280, 2010. [Journal: Review] [CI: 104] [IF: 5,1]
DOI: 10.1016/j.bbalip.2010.01.001 SCOPUS: 76349092667. .
Luoma A.M., Kuo F., Cakici O., Crowther M.N., Denninger A.R., Avila R.L., Brites P., Kirschner D.A.,
Plasmalogen phospholipids protect internodal myelin from oxidative damage. Free Radical Biology and Medicine84:296-310, 2015. [Journal: Article] [CI: 26] [IF: 5,8]
DOI: 10.1016/j.freeradbiomed.2015.03.012 SCOPUS: 84929162848. .
Mar F.M., da Silva T.F., Morgado M.M., Rodrigues L.G., Rodrigues D., Pereira M.I.L., Marques A., Sousa V.F., Coentro J., Sá-Miranda C., Sousa M.M., Brites P.,
Myelin Lipids Inhibit Axon Regeneration Following Spinal Cord Injury: a Novel Perspective for Therapy. Molecular Neurobiology53(2):1052-1064, 2016. [Journal: Article] [CI: 9] [IF: 6,2]
DOI: 10.1007/s12035-014-9072-3 SCOPUS: 84958225895. .
Brites P., Mooyer P.A.W., El Mrabet L., Waterham H.R., Wanders R.J.A.,
Plasmalogens participate in very-long-chain fatty acid-induced pathology. Brain132(2):482-492, 2009. [Journal: Article] [CI: 71] [IF: 9,5]
DOI: 10.1093/brain/awn295 SCOPUS: 60149094802. .
Brites P., Ferreira A.S., da Silva T.F., Sousa V.F., Malheiro A.R., Duran M., Waterham H.R., Baes M., Wanders R.J.A.,
Alkyl-glycerol rescues plasmalogen levels and pathology of ether-phospholipid deficient mice. PLoS ONE6(12):, 2011. [Journal: Article] [CI: 60] [IF: 4,1]
DOI: 10.1371/journal.pone.0028539 SCOPUS: 82755170548. .
Da Silva T.F., Sousa V.F., Malheiro A.R., Brites P.,
The importance of ether-phospholipids: A view from the perspective of mouse models. Biochimica et Biophysica Acta - Molecular Basis of Disease1822(9):1501-1508, 2012. [Journal: Review] [CI: 50] [IF: 4,9]
DOI: 10.1016/j.bbadis.2012.05.014 SCOPUS: 84864039497. .
Brites P., Waterham H.R., Wanders R.J.A.,
Functions and biosynthesis of plasmalogens in health and disease. Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids1636(2-3):219-231, 2004. [Journal: Review] [CI: 252] [IF: 5]
DOI: 10.1016/j.bbalip.2003.12.010 SCOPUS: 2942633430. .
Teixeira C.A., Miranda C.O., Sousa V.F., Santos T.E., Malheiro A.R., Solomon M., Maegawa G.H., Brites P., Sousa M.M.,
Early axonal loss accompanied by impaired endocytosis, abnormal axonal transport, and decreased microtubule stability occur in the model of Krabbe's disease. Neurobiology of Disease66:92-103, 2014. [Journal: Article] [CI: 31] [IF: 5,1]
DOI: 10.1016/j.nbd.2014.02.012 SCOPUS: 84896968554. .