title: Loss of vesicular dopamine release precedes tauopathy in degenerative dopaminergic neurons in a Drosophila model expressing human tau.
abstract: While a number of genome-wide association studies have identified microtubule-associated protein tau as a strong risk factor for Parkinson's disease (PD), little is known about the mechanism through which human tau can predispose an individual to this disease. Here, we demonstrate that expression of human wild-type tau is sufficient to disrupt the survival of dopaminergic neurons in a Drosophila model. Tau triggers a synaptic pathology visualized by vesicular monoamine transporter-pHGFP that precedes both the age-dependent formation of tau-containing neurofibrillary tangle-like pathology and the progressive loss of DA neurons, thereby recapitulating the pathological hallmarks of PD. Flies overexpressing tau also exhibit progressive impairments of both motor and learning behaviors. Surprisingly, contrary to common belief that hyperphosphorylated tau could aggravate toxicity, DA neuron degeneration is alleviated by expressing the modified, hyperphosphorylated tau(E14). Together, these results show that impairment of VMAT-containing synaptic vesicle, released to synapses before overt tauopathy may be the underlying mechanism of tau-associated PD and suggest that correction or prevention of this deficit may be appropriate targets for early therapeutic intervention.
authors.affiliation: Department of Medical Science, Institute of Systems Neuroscience, National Tsing Hua University, 101, Section 2 Kuang-Fu Road, Hsinchu, 30013, Taiwan.
authors.forename: Ting-Han
authors.initials: TH
authors.lastname: Wu
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Lu
authors.forename: Chia-Lung
authors.initials: CL
authors.lastname: Chuang
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wu
authors.forename: Ann-Shyn
authors.initials: AS
authors.lastname: Chiang
authors.forename: David E
authors.initials: DE
authors.lastname: Krantz
authors.forename: Hui-Yun
authors.initials: HY
authors.lastname: Chang
mesh_terms: D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology*; D004330:Drosophila; D006801:Humans; D009043:Motor Activity / Q000502:physiology; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D024801:Tauopathies / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D050493:Vesicular Monoamine Transport Proteins; D016875:tau Proteins