Abstract
BackgroundThe 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.Methodology/Principal FindingsWe 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.Conclusions/SignificanceOur 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.
Highlights
Synucleinopathies are neurodegenerative disorders characterized by the abnormal deposition of a-synuclein (a-syn) in filamentous intracellular inclusions known as Lewy bodies (LBs)
fluorescence lifetime imaging microscopy (FLIM) is a Forster resonance energy transfer (FRET)-based assay that relies on the principle that when two specific fluorophores are in close proximity (,10 nm), the measured fluorescence lifetime of the donor fluorophore is shortened in proportion to the distance between the fluorophores [33,34]
Tau is a microtubule-associated protein localized along the axon that stabilizes microtubules [42,43] and is involved in cellular trafficking and axonal transport [44]. Both are highly expressed in the central nervous system (CNS), are synthesized as native unfolded proteins and have the propensity to form pathological insoluble intracellular aggregates in the CNS in different neurodegenerative diseases
Summary
Synucleinopathies are neurodegenerative disorders characterized by the abnormal deposition of a-synuclein (a-syn) in filamentous intracellular inclusions known as Lewy bodies (LBs). A-syn deposition has been identified in some patients with disorders characterized by prominent tau pathology, such as familial and sporadic AD [19,20,21], Down syndrome [22], progressive supranuclear palsy [23], Parkinsonism dementia complex of Guam [24], and frontotemporal dementia [25,26]. In these cases, colocalization of tau and a-syn aggregates is typically restricted to the amygdala and other limbic areas [27]. It is known that tau and a-syn have pathological synergistic effects on their mutual fibrillization, the underlying biological effects remain unclear
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