Mitochondria and Neurodegenerative Disorders

Ana Cristina Rego

PhD, Group Leader

The research group “Mitochondria and Neurodegenerative Disorders” is focused on understanding cellular and molecular mechanisms associated to mitochondria in early stages of brain neurodegenerative disorders, namely in Huntington’s (HD), Alzheimer’s (AD) and Parkinson’s (PD) diseases. These are chronic, debilitating and age-related brain disorders, characterized by selective cerebral neurodegeneration and cognitive decline. Modified, misfolded and/or mutant proteins affected in these diseases interfere with neuronal function, potentially causing deregulated mitochondrial function and bioenergetics, and altered intracellular redox signaling, namely after activation of glutamate synapses, or lead to defective neurogenesis, impacting on brain cognitive reserve. Although there are several mechanisms by which neurons degenerate, the initial pathways of neuronal dysfunction, occurring before main disease-related symptoms, are largely unknown for each disorder.

In this perspective, by using molecular, cellular, ex-vivo and in vivo approaches, we aim to investigate early modifications affecting mitochondrial function and related signaling linked to redox regulation, glutamate postsynaptic dysfunction and/or modified neurogenesis in different models of neurodegenerative disorders and in peripheral human cells derived from patients and non-affected individuals. The last envisages a closer interaction with the local hospital, particularly in HD and AD. Identification of early disease mechanisms are envisaged to uncover relevant molecular targets for therapeutic intervention, as reviewed by us (Naia et al., 2017, Biochem. Biophys. Res. Commun). Therefore, the group aligns basic and translational research with interest in early disease stages with investigation on neuroprotective therapies based on modifiers of mitochondrial function, glutamate synapse and neurogenesis, using pharmacological compounds, modulation of protein expression and/or gene correction strategies.

Group Members

Group members are: Ana Cristina Rego (PhD, Group Leader), Carla Lopes (PhD), Elisabete Ferreiro (PhD), Ildete Luisa Ferreira (PhD), Lígia Fão, Luana Naia (PhD), Sandra Mota (PhD).

Selected Publications

Petrella LI, Castelhano JM, Ribeiro M, Sereno JV, Gonçalves SI, Laço MN, Hayden MR, Rego AC*, Castelo-Branco M. A whole brain longitudinal study in the YAC128 mouse model of Huntington's disease shows distinct trajectories of neurochemical, structural connectivity and volumetric changes. Hum Mol Genet. 2018 Apr 16. doi: 10.1093/hmg/ddy119. [Epub ahead of print] *co-Corresponding author

Silva AC, Ferreira IL, Hayden MR, Ferreiro E, Rego AC. Characterization of subventricular zone-derived progenitor cells from mild and late symptomatic YAC128 mouse model of Huntington's disease. Biochim Biophys Acta. 2018 Jan;1864(1):34-44.

Naia L, Cunha-Oliveira T, Rodrigues J, Rosenstock TR, Oliveira A, Ribeiro M, Carmo C, Oliveira-Sousa SI, Duarte AI, Hayden MR, Rego AC. Histone Deacetylase Inhibitors Protect Against Pyruvate Dehydrogenase Dysfunction in Huntington's Disease. J Neurosci. 2017 Mar 8;37(10):2776-2794.

Naia L, Rosenstock TR, Oliveira AM, Oliveira-Sousa SI, Caldeira GL, Carmo C, Laço MN, Hayden MR, Oliveira CR, Rego AC. Comparative Mitochondrial-Based Protective Effects of Resveratrol and Nicotinamide in Huntington's Disease Models. Mol Neurobiol. 2017 Sep;54(7):5385-5399.

Perfeito R, Ribeiro M, Rego AC. Alpha-synuclein-induced oxidative stress correlates with altered superoxide dismutase and glutathione synthesis in human neuroblastoma SH-SY5Y cells. Arch Toxicol. 2017 Mar;91(3):1245-1259.

Selected Projects

iPS cells-derived exosomes - impact on mitochondrial (dys)function in Huntington's disease and potential nanodelivery system for microRNA-based therapeutics, Fundação para a Ciência e a Tecnologia (FCT), Portugal, ref. POCI-01-0145-FEDER-029621 (2018-2021).

Transcriptional activity modulation in Alzheimer's disease by inhibitors of histone deacetylases, Fundação para a Ciência e a Tecnologia (FCT), ref. POCI-01-0145-FEDER-032316 (2018-2021)

Exploring striatal postsynaptic SAPAP3 in Huntington’s disease, EHDN-European Huntington’s Disease Network (2018-2019).

Exploring the role of pridopidine on mitochondrial function and dynamics in Huntington’s disease models, TEVA Pharmaceutical Industries Ltd., Petach Tikva, Israel (2017- 2018).

Creation and characterization of neural cells derived from pre-symptomatic and symptomatic Huntington´s disease patient-specific induced pluripotent stem cells”

Supported by: Fundação Luso-Americana para o Desenvolvimento (FLAD), Portugal FLAD LIFE SCIENCE 2020 - FLAD Grants on Portugal-USA collaborative translational project (2015–2017).