Toward an understanding of protein glycation in Parkinson's disease: in vitro and in vivo studies of folding, aggregation and degradation pathways of alpha-synuclein, synphilin-1 and parkin under glycation conditions.

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Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair ltp via NMDA-receptor activation

Publication . Diógenes, Maria José; Dias, Raquel Baptista; Rombo, Diogo M.; Vicente Miranda, Hugo; Maiolino, Francesca; Guerreiro, Patrícia; Nasstrom, Thomas; Franquelim, Henri; Oliveira, Luís M.A.; Castanho, Miguel A. R. B.; Lannfelt, Lars; Bergstrom, Joakim; Ingelsson, Martin; Quintas, Alexandre; Sebastião, Ana M; Lopes, Luisa V.; Outeiro, Tiago

Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of α-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.

2012Journal article

Open 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

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