title: Interactions between Tau and α-synuclein augment neurotoxicity in a Drosophila model of Parkinson's disease.
abstract: Clinical and pathological studies have suggested considerable overlap between tauopathies and synucleinopathies. Several genome-wide association studies have identified alpha-Synuclein (SNCA) and Tau (MAPT) polymorphisms as common risk factors for sporadic Parkinson's disease (PD). However, the mechanisms by which subtle variations in the expression of wild-type SNCA and MAPT influence risk for PD and the underlying cellular events that effect neurotoxicity remain unclear. To examine causes of neurotoxicity associated with the α-Syn/Tau interaction, we used the fruit fly as a model. We utilized misexpression paradigms in three different tissues to probe the α-Syn/Tau interaction: the retina, dopaminergic neurons and the larval neuromuscular junction. Misexpression of Tau and α-Syn enhanced a rough eye phenotype and loss of dopaminergic neurons in fly tauopathy and synucleinopathy models, respectively. Our findings suggest that interactions between α-Syn and Tau at the cellular level cause disruption of cytoskeletal organization, axonal transport defects and aberrant synaptic organization that contribute to neuronal dysfunction and death associated with sporadic PD. α-Syn did not alter levels of Tau phosphorylated at the AT8 epitope. However, α-Syn and Tau colocalized in ubiquitin-positive aggregates in eye imaginal discs. The presence of Tau also led to an increase in urea soluble α-Syn. Our findings have important implications in understanding the cellular and molecular mechanisms underlying α-Syn/Tau-mediated synaptic dysfunction, which likely arise in the early asymptomatic phase of sporadic PD.
authors.affiliation: Mitchell Center for Neurodegenerative Diseases.
authors.forename: Bidisha
authors.initials: B
authors.lastname: Roy
authors.forename: George R
authors.initials: GR
authors.lastname: Jackson
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D003599:Cytoskeleton / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011485:Protein Binding; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
chemical_list: D051844:alpha-Synuclein; D016875:tau Proteins