CNC.IBILI

Neuro6 | Main Goals

Neurodegenerative disorders are a heterogeneous group of chronic brain disorders that usually strike in mid-life and along aging, causing progressive loss of motor and cognitive function. Although clinical manifestations vary, the outcome is the same: patients become incapacitated over a period of years and finally die. Tackling neurodegenerative diseases thus represents an inspiring challenge for our middle-age and aged populations. This is even further relevant since Coimbra was recently recognized as a European Reference Site in Aging.

Thus, our group will conduct basic research studies in neurodegenerative diseases, namely Alzheimer’s disease (AD), Huntington’s disease (HD) and Parkinson’s disease (PD), aimed at increasing our understanding on the causes and mechanisms underlying neuronal and selective brain dysfunction, as well as searching for more effective therapeutics. For this purpose, we will combine basic and translational research, and continue using molecular and cellular approaches (e.g. primary neuronal cultures), as well as studies in animal models (C. elegans and transgenic mice) and human cells and samples; these include peripheral blood cells, induced pluripotent stem cells (iPSCs), brain samples and the generation of novel cybrid lines (which comprise the fusion with patient’s platelets). By using distinct but complementary disease-related models (at molecular, cellular and animal levels) and patient’s samples, we expect to be able to develop innovative studies in the area of translational research.

A first axis of our research is focused on improving our understanding on the molecular basis of neurodegenerative diseases centering on mitochondrial dysfunction underlying primary neuronal dysfunction as a gold-standard of our previous research, as well as related signaling pathways that directly or indirectly affect the function of this key organelle in neurons and eventually lead to neuronal death. These include: i) synaptic dysfunction caused by extrasynaptic versus synaptic NMDARs, composed of GluN2A or GluN2B subunits, through the excitotoxic process closely linked to changes in intracellular calcium homeostasis; ii) oxidative stress and reversible protein oxidation, and its link to nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcriptional changes and synaptic deregulation; iii) mitochondrial-based metabolic changes and transcriptional modifications after modified pyruvate dehydrogenase and sirtuin actions within the organelle; iv) altered mitochondrial dynamics (fission and fusion processes) that highly impact on the processes of organelle elimination and thus neuronal survival. As an ultimate goal we aim to identify molecular targets and thus find opportunities for novel drug intervention strategies. Concordantly, we will continue to evaluate the effects of pharmacological therapies in cell and animal models of neurodegenerative diseases. These include NMDA receptor antagonists (e.g. memantine, ifenprodil) or histone deacetylase (classes I/II and III) modulators.

An emerging branch of our group intends to develop work on adult hippocampal neurogenesis and its impact on cognition and dementia states, commonly affecting neurodegenerative disorders. In particular, adult neurogenesis will be initially studied in the context of AD models considering its relevance for learning and memory. Our unpublished results suggest an early deficit in the production of new neurons, which correlates with early memory deficits in AD mouse models. We will further integrate the current knowledge of the group about alterations in NMDAR signaling pathways, as they can affect neuronal progenitors and function and survival of newly-generated neurons.