Institute of Neuroscience

Staff Profile

Professor Tiago Outeiro

Professor of Neurodegeneration

Background

I am a Professor of Neurodegeneration for the Institute of Neuroscience at Newcastle University. My areas of expertise are protein misfolding, Parkinson's disease, Alzheimer's disease, alpha-synuclein, tau and amyloid-beta.

Research Focus

My research interests are focused on understanding the molecular basis of protein misfolding diseases using a variety of model organisms, from yeast to mice and rats. Our primary focus is on the molecular basis of neurodegenerative disorders. My team has developed key tools and assays for the study of protein-protein interactions that are at the root of protein aggregation, a key event in neurodegeneration. We are now using human brain tissue to investigate molecular signatures associated with disease, to translate our findings into laboratory model systems where we can test novel strategies for therapeutic intervention.

Qualifications

BSc in Biochemistry, University of Porto, Portugal

PhD in Biomedical Sciences, MIT, USA and University of Porto, Portugal

Postdoctoral Research in Neurobiology, MGH, Harvard Medical School, USA

Keywords

Protein misfolding, neurodegeneration, Parkinson's disease, Dementia with Lewy bodies, alpha-synuclein, tau, amyloids.

Google Scholar: Click here.

SCOPUS: Click here.

Research

Research Interests and Contributions

1. Yeast as a model to define the molecular basis of neurodegeneration. I started my scientific career at the University of Leeds, studying the yeast vacuolar ATPase complex. This training was very useful and enabled me to then undertake an ambitious project during my PhD, where I developed the first yeast model of synucleinopathies. This was published in a landmark paper, in Science. Since then, I have continued to use yeast as a toolbox to investigate the basic molecular mechanisms associated with neurodegeneration in Parkinson’s and Huntington’s diseases. In particular, we have recently studied the effect of posttranslational modifications on alpha-synuclein aggregation and toxicity in yeast. Some representative publications include:

a.     Outeiro TF, Lindquist S. Yeast cells provide insight into alpha-synuclein biology and pathobiology. Science. 2003 Dec 5;302(5651):1772-5.

b.     Miller-Fleming L, Antas P, Pais TF, Smalley JL, Giorgini F, Outeiro TF. Yeast DJ-1 superfamily members are required for diauxic-shift reprogramming and cell survival in stationary phase. Proc Natl Acad Sci U S A. 2014 May 13;111(19):7012-7.

c.     Fernandes JT, Tenreiro S, Gameiro A, Chu V, Conde JP*, Outeiro TF*. Modulation of alpha-synuclein toxicity in yeast using a novel microfluidic-based gradient generator. Lab Chip. 2014 Oct 21;14(20):3949-57. *Co-corresponding authors.

d.     Tenreiro S, Reimão-Pinto MM, Antas P, Rino J, Wawrzycka D, Macedo D, Rosado-Ramos R, Amen T, Waiss M, Magalhães F, Gomes A, Santos CN, Kaganovich D, Outeiro TF. Phosphorylation modulates clearance of alpha-synuclein inclusions in a yeast model of Parkinson's disease. PLoS Genet. 2014 May 8;10(5):e1004302.

 

2. Sirtuins and the intersection between aging and neurodegeneration. During my postdoctoral work, I found that pharmacological or genetic inhibition of sirtuin 2, a member of the aging-associated family of sirtuin proteins, was protective in cell and animal of Parkinson’s disease. This was a landmark study published in Science. In my own lab, we have extended those studies and discovered sirtuin 2 can regulate microglial activation and brain inflammation, and we are heavily investigating the molecular mechanisms mediating the effects observed in models of Parkinson’s disease. Representative publications include:

a.     Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 2007 Jul 27;317(5837):516-9.

b.     Pais TF, Szeg? ÉM, Marques O, Miller-Fleming L, Antas P, Guerreiro P, de Oliveira RM, Kasapoglu B, Outeiro TF. The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation. EMBO J. 2013 Oct 2;32(19):2603-16.

c.     Donmez G, Outeiro TF. SIRT1 and SIRT2: emerging targets in neurodegeneration. EMBO Mol Med. 2013 Mar;5(3):344-52.

 

3. Defining the mechanisms of toxicity associated with protein aggregation. A major interest in the field is the definition of the mechanisms of proteotoxicity. My work in yeast and mammalian cell and animal models laid the foundation for studies where we developed novel assays to visualize and measure the effects of protein aggregation in living cells and organisms. Several highly cited articles include:

a.     Outeiro TF, Putcha P, Tetzlaff JE, Spoelgen R, Koker M, Carvalho F, Hyman BT, McLean PJ. Formation of toxic oligomeric alpha-synuclein species in living cells. PLoS One. 2008 Apr 2;3(4):e1867.

b.     Diógenes MJ, Dias RB, Rombo DM, Vicente Miranda H, Maiolino F, Guerreiro P, Näsström T, Franquelim HG, Oliveira LM, Castanho MA, Lannfelt L, Bergström J, Ingelsson M, Quintas A, Sebastião AM, Lopes LV, Outeiro TF. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J Neurosci. 2012 Aug 22;32(34):11750-62.

c.     Blum D, Herrera F, Francelle L, Mendes T, Basquin M, Obriot H, Demeyer D, Sergeant N, Gerhardt E, Brouillet E, Buée L, Outeiro TF. Mutant huntingtin alters Tau phosphorylation and subcellular distribution. Hum Mol Genet. 2015 Jan 1;24(1):76-85.

d.     Villar-Piqué A, Lopes da Fonseca T, Sant'Anna R, Szegö ÉM, Fonseca-Ornelas L, Pinho R, Carija A, Gerhardt E, Masaracchia C, Abad Gonzalez E, Rossetti G, Carloni P, Fernández CO, Foguel D, Milosevic I, Zweckstetter M, Ventura S, Outeiro TF. Environmental and genetic factors support the dissociation between ?-synuclein aggregation and toxicity. Proc Natl Acad Sci U S A. 2016 Oct 5.

e.     Ferreira DG, Temido-Ferreira M, Miranda HV, Batalha VL, Coelho JE, Szegö ÉM, Marques-Morgado I, Vaz SH, Rhee JS, Schmitz M, Zerr I, Lopes LV, Outeiro TF. ?-synuclein interacts with PrP(C) to induce cognitive impairment through mGluR5 and NMDAR2B. Nat Neurosci. 2017 Nov;20(11):1569-1579.

 

4. Defining the contribution of epigenetic regulation in neurodegeneration. The interplay between the environment and genetics is thought to explain the vast majority of cases of Parkinson’s and other neurodegenerative disorders. In addition, the complexity of these disorders suggests additional mechanisms need also be considered. Among these, epigenetic regulation of gene expression, and transcriptional deregulation, appear as major possibilities. I was the senior researcher on several studies already published, and we are further pursuing these lines of research. As examples, I highlight the following articles:

a.     Marques SC, Lemos R, Ferreiro E, Martins M, de Mendonça A, Santana I, Pereira CM*, Outeiro TF*. Epigenetic regulation of BACE1 in Alzheimer's disease patients and in transgenic mice. Neuroscience. 2012 Sep 18;220:256-66. *Co-corresponding authors.

b.     Marques S, Batalha VL, Lopes LV, Outeiro TF. Modulating Alzheimer's disease through caffeine: a putative link to epigenetics. J Alzheimers Dis. 2011;24 Suppl 2:161-71.

c.     Pavlou MA, Pinho R, Paiva I, Outeiro TF. The yin and yang of ?-synuclein-associated epigenetics in Parkinson's disease. Brain. 2016 Aug 31.

d.     Pinho R, Guedes LC, Soreq L, Lobo PP, Mestre T, Coelho M, Rosa MM, Gonçalves N, Wales P, Mendes T, Gerhardt E, Fahlbusch C, Bonifati V, Bonin M, Miltenberger-Miltényi G, Borovecki F, Soreq H, Ferreira JJ, Outeiro TF. Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles. PLoS One. 2016 Jun 20;11(6):e0157852.

 

Teaching

Postgraduate Teaching

I teach regularly in various international Master and PhD programs (Germany, Portugal, Brazil, Croatia, etc.).



Publications