Where Ideas Grow

Neurolipid Biology

ABOUT

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.

 

RESEARCH

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.

Pseudocolored electron microscopy images of synapses in the central nervous system (CNS) and in the peripheral nervous system (PNS)

Team

Selected Publications

Ferreira da Silva T., Granadeiro L.S., Bessa-Neto D., Luz L.L., Safronov B.V., Brites P.,
Plasmalogens regulate the AKT-ULK1 signaling pathway to control the position of the axon initial segment. Progress in Neurobiology205:, 2021. [Journal: Article] [CI: 9] [IF: 10,9]
DOI: 10.1016/j.pneurobio.2021.102123 SCOPUS: 85111800238

Brites P., Sousa M.M.,
Neurons contribute to pathology in a mouse model of Krabbe disease in a cellautonomous manner. PLoS Biology20(7):, 2022. [Journal: Article] [CI: 1] [IF: 9,8]
DOI: 10.1371/journal.pbio.3001706 SCOPUS: 85134360903

Malheiro A.R., Correia B., Ferreira da Silva T., Bessa-Neto D., Van Veldhoven P.P., Brites P.,
Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1-myristyl ether treatment. Brain Pathology29(5):622-639, 2019. [Journal: Article] [CI: 29] [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: 93] [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: 130] [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: 57] [IF: 5,8]
DOI: 10.1016/j.freeradbiomed.2015.03.012 SCOPUS: 84929162848

Qi C., Feng I., Costa A.R., Pinto-Costa R., Neil J.E., Caluseriu O., Li D., Ganetzky R.D., Brasch-Andersen C., Fagerberg C., Hansen L.K., Bupp C., Muraresku C.C., Ruan X., Kang B., Hu K., Zhong R., Brites P., Bhoj E.J., Hill R.S., Falk M.J., Hakonarson H., Kahle K.T., Sousa M.M., Walsh C.A., Zhang X.,
Variants in ADD1 cause intellectual disability, corpus callosum dysgenesis, and ventriculomegaly in humans. Genetics in Medicine24(2):319-331, 2022. [Journal: Article] [CI: 4] [IF: 8,8]
DOI: 10.1016/j.gim.2021.09.014 SCOPUS: 85123344009

Leite S.C., Sampaio P., Sousa V.F., Nogueira-Rodrigues J., Pinto-Costa R., Peters L.L., Brites P., Sousa M.M.,
The Actin-Binding Protein a-Adducin Is Required for Maintaining Axon Diameter. Cell Reports15(3):490-498, 2016. [Journal: Article] [CI: 76] [IF: 8,3]
DOI: 10.1016/j.celrep.2016.03.047 SCOPUS: 84962762309

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: 21] [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: 84] [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: 96] [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: 63] [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: 314] [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: 47] [IF: 5,1]
DOI: 10.1016/j.nbd.2014.02.012 SCOPUS: 84896968554

Ongoing Projects

Unravelling the pathology and disease mechanisms of the newly identified leukoencephalopathy caused by impaired choline transport
Reference: ELA 2021-004I3
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: ELA Research Foundation
From 01-APR-22 to 31-MAR-24