eNeuro. 2021 May 10:ENEURO.0458-20.2021. doi: 10.1523/ENEURO.0458-20.2021. Online ahead of print.
ABSTRACT
Synucleinopathies including Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal intracellular inclusions of α-synuclein (α-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 α-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 α-synuclein and tau proteins interact in vitro Here, we show tau and α-synuclein colocalize at excitatory presynaptic terminals. However, tau heterozygous and tau knockout mice do not show a reduction in fibril-induced α-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 α-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.Significance StatementVariations in the MAPT H1 haplotype are associated with PD, but it is possible that other genes within the H1 haplotype play a role in PD etiology. In vitro studies show α-synuclein and tau interact, leading to synergistic fibrillization. α-Synuclein and tau can co-exist in Lewy bodies. Tau reduction is protective in models of AD and tauopathies and has been suggested as a therapeutic strategy for PD. Here, we show reduction of endogenous tau does not influence formation of templated α-synuclein inclusion formation or loss of dopamine neurons, suggesting that therapeutics directed to tau for PD may be more complicated than tau reduction.
PMID:33972291 | DOI:10.1523/ENEURO.0458-20.2021
