Neurophysiology Neuropsychiatric & Neurodegenerative disorders Da molécula ao homem: desafios, progressos e esperança no conhecimento e tratamento de doenças do cérebro Lisboa | 3 de Março | 2017 @ R&D Unit @ R&D Unit

Health Campus University Hospitals World Heritage Campus Health Campus University Hospitals UC - Biotech BIOCANT Park R&D Center Largest critical mass of biomedical investigators in the CentroPT 227 PhD holders 130 PhD students 28 Technical/Admin. Staff Biomedicine Biotechnology Basic & pre-Clinical Research (interaction with Health Units) Knowledge & Technology Transfer (interaction with Bio/Pharma-Industry) Neuroscience and Brain Diseases Metabolism, Aging and Disease Stem cell-based and Molecular Therapies

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Synapse Biology Research questions PI: Ana Luísa Carvalho (alc@cnc.uc.pt) Research questions The cellular basis of learning and memory - molecular and cellular mechanisms of synaptic plasticity Neuropsychiatric disorders-associated human mutations in genes encoding synaptic proteins – how do these mutations affect synaptic function, circuits and behavior? How do hormones that regulate metabolism impact synaptic plasticity and cognition? Recent publications: Funding: J Cell Biology 212(4): 465-480 [2016] J Neurosci 35:8462-8479 [2015] Cell Reports 7: 1-12 [2014] Proc Natl Acad Sci USA 111: E149-58 [2014]

Mitochondrial dysfunction and signaling in neurodegeneration PI: Ana Cristina Rego (acrego@cnc.uc.pt) Research question: Identification of early mechanisms of neuronal dysfunction in neurodegenerative disorders – current studies in Huntington’s disease (HD) and Alzheimer’s disease (AD) Recent publications: J Neurosci 37(10): 2776-2794 [2017] Hum Mol Genet 26(12): 2231-2246 [2017] Arch Toxicol 91(3): 1245-1259 [2017] Hum Mol Genet 24(7): 1977-1990 [2015] Neurobiol Aging 36(2): 680-692 [2015] Funding:

Mitochondrial dysfunction and signaling in neurodegeneration PI: Ana Cristina Rego (acrego@cnc.uc.pt) • Oxidative stress and mitochondrial dysfunction in animal models and patients of Huntington’s disease (from isolated mitochondria to PET imaging); • Creation and characterization of neural cells derived from pre-symptomatic and symptomatic Huntington’s disease patient-specific induced pluripotent stem cells; • Identification of cellular targets of pridopidine, a drug under clinical trials for Huntington’s disease • Identification of cellular targets of pridopidine, a drug under clinical trials for Huntington’s disease (effects on mitochondrial function and dynamics in animal models of HD) Funding:

Chronic consumption of caffeine as a neuroprotective strategy PI: Rodrigo Cunha (cunharod@gmail.com) Caffeine is the most widely consumed psychoactive drug worldwide. The regular consumption of moderate doses of caffeine is inversely correlated with the incidence of dementia and of depression. These two most common brain disorders have no current effect therapies; thus understanding how caffeine affords protection provides a unique window of opportunity to devise novel therapeutic strategies. This is the major goal of the group ‘Purines at CNC’ using animal models of these brain diseases. We identified adenosine A2A receptors as the targets operated by caffeine to afford neuroprotection. We concluded that blocking A2A receptors prevented memory dysfunction in early Alzheimer’s disease and emotional dysfunction caused by chronic stress, thanks to the support of Portuguese, European and American private and public funds. Funding:

Therapies for Machado Joseph disease Machado Joseph disease (MJD) SCA3 / MJD1 gene transcription 14q32.1 NH2 Mutant ataxin-3 translation (Kawaguchi et al, 1994) 10-51 (normal) 55-87 (disease) (CAG)n PI: Luís Almeida (luispa@ci.uc.pt) Publications Carmona et al (2017) Molecular Therapy Gonçalves et al (2017) Annals of Neurology Cunha-Santos et al (2016) Nature Communications Conceição et al (2016) Biomaterials Nobrega et al (2015) Brain Duarte-Neves et al (2015) Hum Mol Gen Mendonça et al (2015) Brain Dubinsky et al (2014) Cell Metab Gonçalves et al (2013) Ann Neurol Simoes et al (2012) Brain, Simoes et al (2014) Hum Mol Gen Nascimento-Ferreira et al (2011), (2013) Brain Neuronal aggregates of mutant ataxin-3 Neurodegeneration Funding:

Therapies for Machado Joseph disease No therapy is presently available to stop the progression of Machado Joseph disease Gene therapy – Non-invasive gene silencing in the brain PI: Luís Almeida (luispa@ci.uc.pt) Publications Carmona et al (2017) Molecular Therapy Gonçalves et al (2017) Annals of Neurology Cunha-Santos et al (2016) Nature Communications Conceição et al (2016) Biomaterials Nobrega et al (2015) Brain Duarte-Neves et al (2015) Hum Mol Gen Mendonça et al (2015) Brain Dubinsky et al (2014) Cell Metab Gonçalves et al (2013) Ann Neurol Simoes et al (2012) Brain, Simoes et al (2014) Hum Mol Gen Nascimento-Ferreira et al (2011), (2013) Brain Hope from: Stem Cell transplantation Molecular Mechanism driven pharmacology (resveratrol) dietary supplement), based on the work of the group orphan drug designation by EMA) Funding:

(liviasousa@huc.min-saude.pt) Biomarkers in Multiple Sclerosis MS vs. I PI: Carlos B Duarte (cbduarte@ci.uc.pt) 96.9% of original samples correctly classified Research question: Identification of new biomarkers for Multiple Sclerosis in the CSF Lívia Sousa (liviasousa@huc.min-saude.pt) Funding: