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), we are working towards the understanding of pathogenic mechanisms and the discovery and development of Precision Medicine-based therapeutic approaches for this disease. We use both candidate approaches and unbiased screenings to identify small molecules that effectively change the neurotoxic properties of the human mutant protein, and impact the resulting neurological phenotype at the whole organism level – i.e. they reduce the motor impairments caused by expression of the mutant protein. The first line of in vivo analysis is performed using transgenic models of the disease in the nematode Caenorhabditis elegans, a small transparent worm for which large scale studies are easier to perform, and the most promising compounds are then validated in vertebrate models – namely the CMVMJD135 transgenic mouse line. We test repurposing of existing drugs, novel chemical compounds generated by academic and industry collaborators, as well as chemical entities obtained from natural products. In order to contribute for effective translation of our findings to the clinical context, we also work on the development of relevant disease progression and drug response biomarkers, based on analyses of mouse models and human patient samples.

Funding Agency

FCT, National Ataxia Foundation, U.S. Department of Defense

Project Reference

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MSc Student

Bruna Ferreira-Lomba

Research Technician

Main Project Outcomes

Campos, A. B., Duarte-Silva, S., Fernandes, B., Coimbra, B., Campos, J., Monteiro-Fernandes, D., Teixeira-Castro, A., Ambrósio, A. F., & Maciel, P. (2022). Microglial Depletion Has No Impact on Disease Progression in a Mouse Model of Machado-Joseph Disease. Cells, 11(13), 2022. https://doi.org/10.3390/cells11132022

Neves-Carvalho, A., Logarinho, E., Freitas, A., Duarte-Silva, S., Costa, M.doC., Silva-Fernandes, A., Martins, M., Serra, S. C., Lopes, A. T., Paulson, H. L., Heutink, P., Relvas, J. B., & Maciel, P. (2015). Dominant negative effect of polyglutamine expansion perturbs normal function of ataxin-3 in neuronal cells. Human Molecular Genetics, 24(1), 100–117. https://doi.org/10.1093/hmg/ddu422

Duarte-Silva, S., Neves-Carvalho, A., Soares-Cunha, C., Silva, J. M., Teixeira-Castro, A., Vieira, R., Silva-Fernandes, A., & Maciel, P. (2018). Neuroprotective Effects of Creatine in the CMVMJD135 Mouse Model of Spinocerebellar Ataxia Type 3. Movement Disorders : official journal of the Movement Disorder Society, 33(5), 815–826. https://doi.org/10.1002/mds.27292

Chakraborty, A., Tapryal, N., Venkova, T., Mitra, J., Vasquez, V., Sarker, A. H., Duarte-Silva, S., Huai, W., Ashizawa, T., Ghosh, G., Maciel, P., Sarkar, P. S., Hegde, M. L., Chen, X., & Hazra, T. K. (2020). Deficiency in classical nonhomologous end-joining-mediated repair of transcribed genes is linked to SCA3 pathogenesis. Proceedings of the National Academy of Sciences of the United States of America, 117(14), 8154–8165. https://doi.org/10.1073/pnas.1917280117

Costa, M. D. C., Radzwion, M., McLoughlin, H. S., Ashraf, N. S., Fischer, S., Shakkottai, V. G., Maciel, P., Paulson, H. L., & Öz, G. (2020). In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3. Movement Disorders : official journal of the Movement Disorder Society, 35(10), 1774–1786. https://doi.org/10.1002/mds.28140

Vilasboas-Campos, D., Costa, M. D., Teixeira-Castro, A., Rios, R., Silva, F. G., Bessa, C., Dias, A. C. P., & Maciel, P. (2021). Neurotherapeutic effect of Hyptis spp. leaf extracts in Caenorhabditis elegans models of tauopathy and polyglutamine disease: Role of the glutathione redox cycle. Free Radical Biology & Medicine, 162, 202–215. https://doi.org/10.1016/j.freeradbiomed.2020.10.018

Campos, A. B., Duarte-Silva, S., Fernandes, B., das Neves, S. P., Marques, F., Teixeira-Castro, A., Neves-Carvalho, A., Monteiro-Fernandes, D., Portugal, C. C., Socodato, R., Summavielle, T., Ambrósio, A. F., Relvas, J. B., & Maciel, P. (2022). Profiling Microglia in a Mouse Model of Machado-Joseph Disease. Biomedicines, 10(2), 237. https://doi.org/10.3390/biomedicines10020237

Costa, M. D., & Maciel, P. (2022). Modifier pathways in polyglutamine (PolyQ) diseases: from genetic screens to drug targets. Cellular and Molecular Life Sciences : CMLS, 79(5), 274. https://doi.org/10.1007/s00018-022-04280-8

Mayoral-Palarz, K., Neves-Carvalho, A., Duarte-Silva, S., Monteiro-Fernandes, D., Maciel, P., & Khodakhah, K. (2022). Cerebellar neuronal dysfunction accompanies early motor symptoms in spinocerebellar ataxia type 3. Disease Models & Mechanisms, 15(8), dmm049514. https://doi.org/10.1242/dmm.049514