Targeting the glycation defenses as a protective strategy for Parkinson’s disease

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Posttranslational modifications of blood-derived alpha-synuclein as biochemical markers for Parkinson’s disease

Publication . Vicente Miranda, Hugo; Cassio, Rafaela; Correia Guedes, Leonor; Gomes, Marcos António; Chegão, Ana; Miranda, Elisa; Soares, Tiago; Coelho, Miguel; Rosa, Mário Miguel; Ferreira, Joaquim J; Outeiro, Tiago

Parkinson's disease (PD) is a progressive neurodegenerative disorder known for the typical motor features associated. Pathologically, it is characterized by the intracellular accumulation of alpha-synuclein (aSyn) in Lewy bodies and Lewy neurites. Currently, there are no established biochemical markers for diagnosing or for following disease progression, a major limitation for the clinical practice. Posttranslational modifications (PTMs) in aSyn have been identified and implicated on its pathobiology. Since aSyn is abundant in blood erythrocytes, we aimed to evaluate whether PTMs of aSyn in the blood might hold value as a biomarker for PD. We examined 58 patients with PD and 30 healthy age-matched individuals. We found that the levels of Y125 phosphorylated, Y39 nitrated, and glycated aSyn were increased in PD, while those of SUMO were reduced. A combinatory analysis of the levels of these PTMs resulted in an increased sensitivity, with an area under curve (AUC) of 0.843 for PD versus healthy controls, and correlated with disease severity and duration. We conclude that the levels of these selected PTMs hold strong potential as biochemical markers for PD. Ultimately, our findings might facilitate the monitoring of disease progression in clinical trials, opening the possibility for developing more effective therapies against PD.

2017Journal article

Open access

A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease

Publication . Fonseca-Gomes, João; Costa-Coelho, Tiago; Ferreira-Manso, Mafalda; Inteiro-Oliveira, Sara; Vaz, Sandra H.; Alemãn-Serrano, Nuno; Atalaia Barbacena, Henrique; Ribeiro Rodrigues, Leonor; Ramalho, Rita Mira; Climaco Pinto, Rui; Vicente Miranda, Hugo; Tanqueiro, Sara; de Almeida-Borlido, Carolina; Ramalho, Maria João; Miranda-Lourenço, Catarina; Belo, Rita F.; Ferreira, Catarina B.; Neves, Vera; Rombo, Diogo M.; Viais, Ricardo; Umemori, Juzoh; Martins, Ivo C.; Jerónimo-Santos, André; Caetano, António; Manso, Nuno; Mäkinen, Petra; Marttinen, Mikael; Takalo, Mari; Bremang, Michael; Pike, Ian; Haapasalo, Annakaisa; Loureiro, Joana A.; Pereira, Maria Carmo; Santos, Nuno C.; Outeiro, Tiago; Castanho, Miguel A. R. B.; Fernandes, Adelaide; Hiltunen, Mikko; Duarte, Carlos B.; Castrén, Eero; De Mendonça, Alexandre; Sebastião, Ana M; Rodrigues, Tiago M.; Diógenes, Maria José

In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.

2024Journal article

Open access

α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B

Publication . Ferreira, Diana; Temido Ferreira, Mariana; Vicente Miranda, Hugo; Batalha, Vânia; Coelho, Joana E; Szegö, Éva M; Marques-Morgado, Inês; Vaz, Sandra H.; Rhee, Jeong Seop; Schmitz, Matthias; Zerr, Inga; Lopes, Luisa V.; Outeiro, Tiago

Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of α-synuclein (aSyn) in intracellular inclusions known as Lewy bodies. Prefibrillar soluble aSyn oligomers, rather than larger inclusions, are currently considered to be crucial species underlying synaptic dysfunction. We identified the cellular prion protein (PrPC) as a key mediator in aSyn-induced synaptic impairment. The aSyn-associated impairment of long-term potentiation was blocked in Prnp null mice and rescued following PrPC blockade. We found that extracellular aSyn oligomers formed a complex with PrPC that induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). aSyn engagement of PrPC and Fyn activated NMDA receptor (NMDAR) and altered calcium homeostasis. Blockade of mGluR5-evoked phosphorylation of NMDAR in aSyn transgenic mice rescued synaptic and cognitive deficits, supporting the hypothesis that a receptor-mediated mechanism, independent of pore formation and membrane leakage, is sufficient to trigger early synaptic damage induced by extracellular aSyn.

2017Journal article

Restricted access

Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

Publication . Miranda, Hugo Vicente; Szego, Éva M.; Oliveira, Luís M. A.; Breda, Carlo; Darendelioglu, Ekrem; Oliveira, Rita M. de; Ferreira, Diana G.; Gomes, Marcos A.; Rott, Ruth; Oliveira, Márcia; Munari, Francesca; Enguita, Francisco J.; Simões, Tânia; Rodrigues, Eva F.; Heinrich, Michael; Martins, Ivo C.; Zamolo, Irina; Riess, Olaf; Cordeiro, Carlos; Freire, Ana Ponces; Lashuel, Hilal A.; Santos, Nuno C.; Lopes, Luisa V.; Xiang, Wei; Jovin, Thomas M.; Penque, Deborah; Engelender, Simone; Zweckstetter, Markus; Klucken, Jochen; Giorgini, Flaviano; Quintas, Alexandre; Outeiro, Tiago F.

α-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of α-synuclein, reducing membrane binding, impaired the clearance of α-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of α-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions

2017Journal article

Restricted access