Lab

Patricia Maciel's Lab

Institution: University of Minho

About the lab

The goal of our research is to understand the genetic basis of nervous system function and dysfunction, with a strong focus on human neurological disease, using molecular genetics, genomics, transcriptomics, proteomics, cell biology and behavioral analysis. We study neurodegenerative and neurodevelopmental disorders. The disease models we develop in C. elegans and mouse can, once validated, be used to search for therapeutic targets and test the efficacy of therapeutic strategies.
Given our longterm interest in the function of the de-ubiquitylating enzyme ataxin-3 (ATXN3), we have also started looking at other components of the ubiquitin proteasome system and at the role of ubiquitin signalling in general for nervous system development, function and dysfunction.

Featured projects (3)

Project
We aim to understand the different roles of ubiqutin signalling for nervous system function and dysfunction, with a strong focus on translation of fundamental biology to human neurological diseases.
Project
To understand the mechanism underlying this genetically defined neurodegenerative disorder and to develop therapeutic approaches to counteract it.
Project
We aim to identify novel genetic causes of neurodevelopmental diseases such as intellectual disability, epilepsy and autism, and to develop cellular and animal models for the study of these diseases that make them tractable from the drug discovery standpoint.

Featured research (1)

The atypical antipsychotic aripiprazole is a Food and Drug Administration-approved drug for the treatment of psychotic, mood, and other psychiatric disorders. Previous drug discovery efforts pinpointed aripiprazole as an effective suppressor of Machado–Joseph disease (MJD) pathogenesis, as its administration resulted in a reduced abundance and aggregation of mutant Ataxin-3 (ATXN3) proteins. Dopamine partial agonism and functional selectivity have been proposed as the main pharmacological mechanism of action of aripiprazole in the treatment of psychosis; however, this mechanism remains to be determined in the context of MJD. Here, we focus on confirming the efficacy of aripiprazole to reduce motor dysfunction in vivo, using a Caenorhabditis elegans (C. elegans) model of MJD, and on unveiling the drug targets required for its positive action against mutant ATXN3 pathogenesis. We employed pharmacogenetics and pharmacological approaches to identify which dopamine and serotonin receptors are critical for aripiprazole-mediated improvements in motor function. We demonstrated that dopamine D2-like and serotonin 5-HT1A and 5-HT2A receptors play important roles in this process. Our findings strengthen the relevance of dopaminergic and serotoninergic signaling modulation against mutant ATXN3-mediated pathogenesis. The identification of aripiprazole’s cellular targets, relevant for MJD and perhaps other neurodegenerative diseases, may pave the way for prospective drug discovery and development campaigns aiming to improve the features of this prototypical compound and reduce side effects not negligible in the case of aripiprazole.

Lab head

Patricia Maciel
Department
  • School of Medicine
About Patricia Maciel
  • The goal of my research is to understand the genetic basis of nervous system function and dysfunction, with a strong focus on human neurological disease, using molecular genetics, genomics, transcriptomics, proteomics, cell biology and behavioral analysis. We study neurodegenerative and neurodevelopmental disorders. The disease models we develop in C. elegans and mouse can, once validated, be used to search for therapeutic targets and test the efficacy of therapeutic strategies.

Members (17)

Andreia Teixeira-Castro
  • University of Minho
Sara Duarte-Silva
  • University of Minho
Marta D Costa
  • University of Minho
Andreia Carvalho
  • University of Minho
Bruno Almeida
  • University of Minho
Jorge Diogo Da Silva
  • University of Minho
Joana Pereira-Sousa
  • University of Minho
Daniela Vilasboas-Campos
  • University of Minho

Alumni (5)

Teresa Temudo
  • Centro Materno Infantil do Norte, Porto, Portugal
Maria do Carmo Costa
  • University of Michigan
Anabela Silva-Fernandes
  • University of Minho
Anabela Ferro
  • University of Porto