groups:uncm:index - Instituto de Medicina Molecular

Research Interests

Our research interests are focused on the understanding of the molecular mechanisms which lead to neurodegeneration in diseases such as Parkinson's, Huntington's, or Alzheimer's disease. These diseases are intimately associated with protein misfolding and aggregation in specific regions of the brain.

Because the molecular pathways involved in protein homeostasis are highly conserved, we employ a wide variety of model organisms, from the simple but powerful budding yeast to mammalian cell culture and mice.

Our ultimate goals are to develop novel therapeutic approaches for these and other related disorders. We are working closely together with clinicians in order to accelerate drug discovery efforts, translating basic research into clinical applications that will improve the lives of patients.

Coordinator / Principal Investigator

Tiago Fleming Outeiro, Ph.D. - Principal Investigator, Auxiliary Professor in Physiology, Faculty of Medicine

Research Team

Teresa Pais, Ph.D. - Staff Scientist
Sandra Tenreiro, Ph.D. - Postdoctoral Fellow
Rita Machado de Oliveira, Ph.D. - Postdoctoral Fellow
Joana Matos, Ph.D. - Postdoctoral Fellow
Zrinka Marjanovic, Ph.D. - Postdoctoral Fellow
Mónica Cunha, Ph.D. - Postdoctoral Fellow
Leonor Fleming - Ph.D. Student
Susana Gonçalves - Ph.D. Student
Oldriska Marques - Ph.D. student
Olga Sin - Master's student
Andreia Peixoto - Technician
Ana Osório Oliveira - Technician
Patrícia Guerreiro - PhD Student
Federico Herrera - Postdoctoral Fellow
Hugo Miranda - Postdoctoral Fellow

Research Areas

Protein misfolding, oligomerization and aggregation
Yeast models for Parkinson’s and Huntington’s disease
Modulators of protein aggregation and toxicity
Microscopy-based methods for investigating the molecular nature of the toxic proteinaceous species in Parkinson’s disease
In vivo imaging using multi-photon microscopy
Development of novel therapeutic approaches for neurodegenerative disease
Novel Biomarkers for AD, PD, and HD

Our Rationale

At the UNCM we use a variety of model organisms and molecular approaches to uderstand the basis of disease, with the goal of opening novel avenues for therapeutic intervention.

Fluorescence Lifetime Imaging Microscopy

FLIM is a powerful technique to measure protein-protein interactions, and is based on the FRET principle, as shown below.
We apply FLIM to study the molecular interactions at the root of protein aggregation, a central process in neurodegeneration.

Ongoing Research Projects

SirT2 as a Drug Target in Parkinson's Disease - funded by Michael J. Fox Foundation, USA.
Unraveling the genetic basis for alpha-synuclein oligomerization in living cells using bimolecular fluorescence complementation - funded by Michael J. Fox Foundation, USA.
Deciphering the Molecular Role of DJ-1 in Parkinson's disease - funded by Fundação Calouste Gulbenkian.
NEUROFOLD, Uncovering the Molecular Basis of Neurodegenerative Disorders - funded by Marie Curie Program, European Commission.

Selected Publications

Outeiro TF, Ferreira J., Current and Future Therapeutic Strategies for Parkinson's Disease,
Curr Pharm Des. 2009 Sep 15. [Epub ahead of print]

Outeiro TF, Klucken J, Bercury K, Tetzlaff J, Putcha P, Oliveira LM, Quintas
A, McLean PJ, Hyman BT. Dopamine-induced conformational changes in
alpha-synuclein. PLoS One. 2009 Sep 4;4(9):e6906. PubMed PMID: 19730729; PubMed
Central PMCID: PMC2731858.

Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro TF, Pepivani I, Ng J,
Schulz-Schaeffer W, Kretzschmar HA, McLean PJ, Trenkwalder C, Sarracino DA,
Vonsattel JP, Locascio JJ, El-Agnaf OM, Schlossmacher MG. Direct quantification
of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with
neurodegeneration. Exp Neurol. 2008 Oct;213(2):315-25. Epub 2008 Jun 14. PubMed
PMID: 18625222.

Tetzlaff JE, Putcha P, Outeiro TF, Ivanov A, Berezovska O, Hyman BT, McLean
PJ. CHIP targets toxic alpha-Synuclein oligomers for degradation. J Biol Chem.
2008 Jun 27;283(26):17962-8. Epub 2008 Apr 24. PubMed PMID: 18436529.

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.
PMID: 18382657 [PubMed - in process]

Fleming J, Outeiro TF, Slack M, Lindquist SL, Bulawa CE.
Detection of compounds that rescue rab1-synuclein toxicity.
Methods Enzymol. 2008;439:339-51.
PMID: 18374176 [PubMed - in process]

Outeiro TF, Marques O, Kazantsev A.
Therapeutic role of sirtuins in neurodegenerative disease.
Biochim Biophys Acta. 2008 Mar 7; [Epub ahead of print]
PMID: 18373985 [PubMed - as supplied by publisher]

Miller-Fleming L, Giorgini F, Outeiro TF.
Yeast as a model for studying human neurodegenerative disorders.
Biotechnol J. 2008 Mar;3(3):325-38. Review. Erratum in: Biotechnol J. 2008
Mar;3(3):421.
PMID: 18228539 [PubMed - indexed for MEDLINE]

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. Epub 2007 Jun 21.
PMID: 17588900 [PubMed - indexed for MEDLINE]

Grammatopoulos TN, Outeiro TF, Hyman BT, Standaert DG. Angiotensin II protects against alpha-synuclein toxicity and reduces protein aggregation in vitro.
Biochem Biophys Res Commun. 2007 Nov 23;363(3):846-51. Epub 2007 Sep 21.
PMID: 17900533 [PubMed - in process]

Outeiro TF, Grammatopoulos TN, Altmann S, Amore A, Standaert DG, Hyman BT,
Kazantsev AG. Pharmacological inhibition of PARP-1 reduces alpha-synuclein- and MPP+-induced
cytotoxicity in Parkinson's disease in vitro models.
Biochem Biophys Res Commun. 2007 Jun 8;357(3):596-602. Epub 2007 Apr 5.
PMID: 17449015 [PubMed - indexed for MEDLINE]

Outeiro TF, Tetzlaff J. Mechanisms of disease II: cellular protein quality control.
Semin Pediatr Neurol. 2007 Mar;14(1):15-25. Review.
PMID: 17331880 [PubMed - indexed for MEDLINE]

St Martin JL, Klucken J, Outeiro TF, Nguyen P, Keller-McGandy C,
Cantuti-Castelvetri I, Grammatopoulos TN, Standaert DG, Hyman BT, McLean PJ. Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra.
J Neurochem. 2007 Mar;100(6):1449-57. Epub 2007 Jan 4.
PMID: 17241127 [PubMed - indexed for MEDLINE]

Outeiro TF, Klucken J, Strathearn KE, Liu F, Nguyen P, Rochet JC, Hyman BT,
McLean PJ. Small heat shock proteins protect against alpha-synuclein-induced toxicity and
aggregation.
Biochem Biophys Res Commun. 2006 Dec 22;351(3):631-8. Epub 2006 Oct 26.
PMID: 17081499 [PubMed - indexed for MEDLINE]

Klucken J, Outeiro TF, Nguyen P, McLean PJ, Hyman BT. Detection of novel intracellular alpha-synuclein oligomeric species by fluorescence lifetime imaging.
FASEB J. 2006 Oct;20(12):2050-7.
PMID: 17012257 [PubMed - indexed for MEDLINE]

Outeiro TF. A bridge from Portugal to the States.
Nature. 2006 Sep 7;443(7107):118. No abstract available.
PMID: 17001768 [PubMed - indexed for MEDLINE]

Outeiro TF, Giorgini F. Yeast as a drug discovery platform in Huntington's and Parkinson's diseases.
Biotechnol J. 2006 Mar;1(3):258-69. Review.
PMID: 16897706 [PubMed - indexed for MEDLINE]

Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ,
Young AB, Housman DE, Kazantsev AG. Pharmacological promotion of inclusion formation: a therapeutic approach for
Huntington's and Parkinson's diseases.
Proc Natl Acad Sci U S A. 2006 Mar 14;103(11):4246-51. Epub 2006 Mar 6.
PMID: 16537516 [PubMed - indexed for MEDLINE]

Derkatch IL, Uptain SM, Outeiro TF, Krishnan R, Lindquist SL, Liebman SW. Effects of Q/N-rich, polyQ, and non-polyQ amyloids on the de novo formation of the [PSI+] prion in yeast and aggregation of Sup35 in vitro.
Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12934-9. Epub 2004 Aug 23.
PMID: 15326312 [PubMed - indexed for MEDLINE]

Outeiro TF, Muchowski PJ. Molecular genetics approaches in yeast to study amyloid diseases.
J Mol Neurosci. 2004;23(1-2):49-60. Review.
PMID: 15126692 [PubMed - indexed for MEDLINE]

Rochet JC, Outeiro TF, Conway KA, Ding TT, Volles MJ, Lashuel HA, Bieganski
RM, Lindquist SL, Lansbury PT. Interactions among alpha-synuclein, dopamine, and biomembranes: some clues for
understanding neurodegeneration in Parkinson's disease.
J Mol Neurosci. 2004;23(1-2):23-34. Review.
PMID: 15126689 [PubMed - indexed for MEDLINE]

Outeiro TF, Lindquist S. Yeast cells provide insight into alpha-synuclein biology and pathobiology.
Science. 2003 Dec 5;302(5651):1772-5.
PMID: 14657500 [PubMed - indexed for MEDLINE]

Willingham S, Outeiro TF, DeVit MJ, Lindquist SL, Muchowski PJ. Yeast genes that enhance the toxicity of a mutant huntingtin fragment or alpha-synuclein.
Science. 2003 Dec 5;302(5651):1769-72.
PMID: 14657499 [PubMed - indexed for MEDLINE]

Resende CG, Outeiro TF, Sands L, Lindquist S, Tuite MF. Prion protein gene polymorphisms in Saccharomyces cerevisiae.
Mol Microbiol. 2003 Aug;49(4):1005-17.
PMID: 12890024 [PubMed - indexed for MEDLINE]