Templated α-synuclein inclusion formation is independent of endogenous tau

Synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal intracellular inclusions of a-synuclein (a-synuclein). Parkinson's disease dementia (PDD) and DLB are collectively the second most common cause of neurodegenerative dementia. In addition to associated inclusions, Lewy body diseases have dopaminergic neurodegeneration, motor defects and cognitive changes. The microtubule-associated protein tau has been implicated in LBDs, but the exact role of the protein and how it influences formation of a-synuclein inclusions is unknown. Reducing endogenous tau levels is protective in multiple models of Alzheimer's disease (AD), tauopathies, and in some transgenic synucleinopathy mouse models. Recombinant asynuclein and tau proteins interact in vitro. Here, we show tau and a-synuclein colocalize at excitatory presynaptic terminals. However, tau heterozygous and tau knockout mice do not show a reduction in fibril-induced a-synuclein inclusions formation in primary cortical neurons, or after intrastriatal injections of fibrils at 1.5 month or 6 months later. At 6 months following intrastriatal injections, wild type, tau heterozygous and tau knockout mice showed a 50% reduction in dopamine neurons in the SNc compared to mice injected with a-synuclein monomer, but there were no statistically significant differences across genotypes. These data suggest the role of tau in the pathogenesis of LBDs is distinct from AD, and Lewy pathology formation may be independent of endogenous tau.

Automated summary

Synucleinopathies, such as Parkinson's disease and Dementia with Lewy bodies, are characterized by neuronal inclusions of α-synuclein. Tau protein has been implicated in Lewy body diseases, but its exact role and influence on α-synuclein formation remains unknown. Studies have shown that reducing tau levels is protective in certain neurodegenerative diseases, but the relationship between tau and α-synuclein inclusions is complex and may differ from Alzheimer's disease.