Translational Neurogenetics

The goal of our research is to understand the genetic basis of human neurological diseases, using molecular genetics, genomics, transcriptomics, proteomics, cell biology, electrophysiology and behavioral analysis, and to apply this knowledge to the clinical context. We study neurodegenerative and neurodevelopmental disorders, from gene identification in human patient cohorts to mechanistic studies and preclinical drug testing. For this we develop disease models using cultured cells, C. elegans and mice, which, once validated, can be used to search for therapeutic targets and test the efficacy of therapeutic strategies – based on novel synthetic molecules, natural products and repurposed drugs.

Within our studies of disease mechanisms, a topic of particular relevance is the regulation of protein homeostasis within neurons, through the action of a network of protein folding and protein degradation promoting molecules. The function of these molecules in neuronal cells is of interest to us from a fundamental science perspective but also as potential drug targets. We have acquired expertise and developed relevant tools for the study of these pathways, from chaperones to the ubiquitin-proteasome system, and autophagy, as well as to address degradation-unrelated ubiquitin signalling in the nervous system. We are also working on new small-molecule based therapeutic modalities for neurodegenerative diseases that harness these endogenous targeted protein degradation mechanisms or target selected protein-protein interactions.

PhD Student

Lídia Nunes-Carvalho

MSc Student

Bruna Ferreira-Lomba

Research Technician

Team Members

Projects

Patricia Maciel

Genetics of Neurodevelopmental Disorders

Our multidisciplinary research team aims at dentifying and validating novel genetic causes of neurodevelopmental disorders in human patients, taking advantage of clinically well characterized patient cohorts and…

Patricia Maciel

Pathogenesis and Development of Therapeutics for Machado-Joseph disease

Departing from previous work in which we developped cellular and animal models of Machado-Joseph disease, a neurodegenerative disorder caused by expansion of a polyglutamine tract in the protein ataxin-3 (ATXN3)…

Patricia Maciel

Pathogenesis and Development of Therapeutics for Neurodevelopmental Disorders

Our goal is to uncover mechanisms of disease and to test potential therapeutic approaches for disorders of human neurodevelopment, including intellectual disability (ID) and autism, but also early onset movement disorders…

Andreia Teixeira-Castro

Serotonin signaling and proteostasis

This project addresses an unmet medical need- the lack of effective treatment for any of the aging-associated neurodegenerative diseases. Due to the worldwide aging of the population, by 2050 it is expected that over 135 million people…

Success Story

Our team has a strong and internationally recognized scientific expertise in Machado-Joseph disease – a rare neurodegenerative disease within the group of polyglutamine diseases– and in proteostasis, related to normal aging and to aging-related neurodegenerative disorders. We have developed highly relevant animal models of this disease in C. elegans and mouse, that mimick the core features of the human disease, from pathology to motor phenotype. We optimized a setup for medium-throughput drug screening based on the C. elegans model that has allowed the discovery of highly relevant therapeutic candidates and provided novel clues to disease pathogenesis mechanisms. Three of the molecules identified using this approach – citalopram/escitalopram, creatine and tauroursodeoxycholic acid (TUDCA) – are easily translatable to the clinical context, in a drug repurposing approach, given their known safety, and thus may allow closing this virtuous circle with impact on patient care.

Selected Research Outputs

Duarte-Silva, S.*, Da Silva, J. D.*, Monteiro-Fernandes, D.*, Costa, M. D., Neves-Carvalho, A., Raposo, M., Soares-Cunha, C., Correia, J. S., Nogueira-Goncalves, G., Fernandes, H. S., Oliveira, S., Ferreira-Fernandes, A. R., Rodrigues, F., Pereira-Sousa, J., Vilasboas-Campos, D., Guerreiro, S., Campos, J., Meireles-Costa, L., Rodrigues, C. M. P., Cabantous, S., Sousa, S. F., Lima, M., Teixeira-Castro, A., & Maciel, P. (2024). Glucocorticoid receptor-dependent therapeutic efficacy of tauroursodeoxycholic acid in preclinical models of spinocerebellar ataxia type 3. The Journal of Clinical Investigation, 134(5), e162246. https://doi.org/10.1172/JCI162246

Fu, J. M., F. K. Satterstrom, M. Peng, H. Brand, R. L. Collins, S. Dong, B. Wamsley, L. Klei, L. Wang, S. P. Hao, C. R. Stevens, C. Cusick, M. Babadi, E. Banks, B. Collins, S. Dodge, S. B. Gabriel, L. Gauthier, S. K. Lee, L. Liang, A. Ljungdahl, B. Mahjani, L. Sloofman, A. N. Smirnov, M. Barbosa, C. Betancur, A. Brusco, B. H. Y. Chung, E. H. Cook, M. L. Cuccaro, E. Domenici, G. B. Ferrero, J. J. Gargus, G. E. Herman, I. Hertz-Picciotto, P. Maciel, D. S. Manoach, M. R. Passos-Bueno, A. M. Persico, A. Renieri, J. S. Sutcliffe, F. Tassone, E. Trabetti, G. Campos, S. Cardaropoli, D. Carli, M. C. Y. Chan, C. Fallerini, E. Giorgio, A. C. Girardi, E. Hansen-Kiss, S. L. Lee, C. Lintas, Y. Ludena, R. Nguyen, L. Pavinato, M. Pericak-Vance, I. N. Pessah, R. J. Schmidt, M. Smith, C. I. S. Costa, S. Trajkova, J. Y. T. Wang, M. H. C. Yu, B. Aleksic, M. Artomov, E. Benetti, M. Biscaldi-Schafer, A. D. Børglum, A. Carracedo, A. G. Chiocchetti, H. Coon, R. N. Doan, M. Fernández-Prieto, C. M. Freitag, S. Gerges, S. Guter, D. M. Hougaard, C. M. Hultman, S. Jacob, M. Kaartinen, A. Kolevzon, I. Kushima, T. Lehtimäki, C. L. Rizzo, N. Maltman, M. Manara, G. Meiri, I. Menashe, J. Miller, N. Minshew, M. Mosconi, N. Ozaki, A. Palotie, M. Parellada, K. Puura, A. Reichenberg, S. Sandin, S. W. Scherer, S. Schlitt, L. Schmitt, K. Schneider-Momm, P. M. Siper, P. Suren, J. A. Sweeney, K. Teufel, M. del Pilar Trelles, L. A. Weiss, R. Yuen, D. J. Cutler, S. De Rubeis, J. D. Buxbaum, M. J. Daly, B. Devlin, K. Roeder, S. J. Sanders, M. E. Talkowski, C. The Autism Sequencing, G. Broad Institute Center for Common Disease and P.-B. C. i (2022). Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nature Genetics, 54(9), 1320-1331. https://doi.org/10.1038/s41588-022-01104-0

Satterstrom, F. K., J. A. Kosmicki, J. Wang, M. S. Breen, S. De Rubeis, J. Y. An, M. Peng, R. Collins, J. Grove, L. Klei, C. Stevens, J. Reichert, M. S. Mulhern, M. Artomov, S. Gerges, B. Sheppard, X. Xu, A. Bhaduri, U. Norman, H. Brand, G. Schwartz, R. Nguyen, E. E. Guerrero, C. Dias, C. Betancur, E. H. Cook, L. Gallagher, M. Gill, J. S. Sutcliffe, A. Thurm, M. E. Zwick, A. D. Børglum, M. W. State, A. E. Cicek, M. E. Talkowski, D. J. Cutler, B. Devlin, S. J. Sanders, K. Roeder, M. J. Daly and J. D. Buxbaum (2020). "Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism." Cell 180(3): 568-584.e523.

Teixeira-Castro, A.*, Jalles, A.*, Esteves, S.*, Kang, S., da Silva Santos, L., Silva-Fernandes, A., Neto, M. F., Brielmann, R. M., Bessa, C., Duarte-Silva, S., Miranda, A., Oliveira, S., Neves-Carvalho, A., Bessa, J., Summavielle, T., Silverman, R. B., Oliveira, P., Morimoto, R. I., & Maciel, P. (2015). Serotonergic signalling suppresses ataxin 3 aggregation and neurotoxicity in animal models of Machado-Joseph disease. Brain: a journal of neurology, 138(Pt 11), 3221–3237. https://doi.org/10.1093/brain/awv262