Tau enhances α-synuclein aggregation and toxicity in cellular models of synucleinopathy

• Published in: PloS one 2011-10, Vol.6 (10), p.e26609
• Main Authors: Badiola, Nahuai, de Oliveira, Rita Machado, Herrera, Federico, Guardia-Laguarta, Cristina, Gonçalves, Susana A, Pera, Marta, Suárez-Calvet, Marc, Clarimon, Jordi, Outeiro, Tiago Fleming, Lleó, Alberto
• Format: Article
• Language: English
• Subjects: Agglomeration; Aggregates; alpha-Synuclein - biosynthesis; alpha-Synuclein - metabolism; alpha-Synuclein - toxicity; Biological effects; Biology; Blotting, Western; Brain; Cell culture; Cell Line; Central nervous system; Confocal microscopy; Cytotoxicity; Dementia; Dementia disorders; Enzyme-Linked Immunosorbent Assay; Fibrillogenesis; Fluorescence Resonance Energy Transfer; Humans; Immunoglobulins; Lewy bodies; Medicine; Microscopy; Microscopy, Confocal; Models, Biological; Molecular Weight; Movement disorders; Neuroblastoma; Neurodegeneration; Neurodegenerative diseases; Neurological diseases; Neuropathology; Neurosciences; Neurotoxicity; Parkinson's disease; Parkinsons disease; Pathology; Phosphorylation; Physics; Protein folding; Proteins; Synergistic effect; Synergistic effects; Synuclein; Tau protein; tau Proteins - physiology; Toxicity; Transfection
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0026609

The simultaneous accumulation of different misfolded proteins in the central nervous system is a common feature in many neurodegenerative diseases. In most cases, co-occurrence of abnormal deposited proteins is observed in different brain regions and cell populations, but, in some instances, the proteins can be found in the same cellular aggregates. Co-occurrence of tau and α-synuclein (α-syn) aggregates has been described in neurodegenerative disorders with primary deposition of α-syn, such as Parkinson's disease and dementia with Lewy bodies. Although it is known that tau and α-syn have pathological synergistic effects on their mutual fibrillization, the underlying biological effects remain unclear. We used different cell models of synucleinopathy to investigate the effects of tau on α-syn aggregation. Using confocal microscopy and FRET-based techniques we observed that tau colocalized and interacted with α-syn aggregates. We also found that tau overexpression changed the pattern of α-syn aggregation, reducing the size and increasing the number of aggregates. This shift was accompanied by an increase in the levels of insoluble α-syn. Furthermore, co-transfection of tau increased secreted α-syn and cytotoxicity. Our data suggest that tau enhances α-syn aggregation and toxicity and disrupts α-syn inclusion formation. This pathological synergistic effect between tau and α-syn may amplify the deleterious process and spread the damage in neurodegenerative diseases that show co-occurrence of both pathologies.