Interactions between Tau and α-synuclein augment neurotoxicity in a Drosophila model of Parkinson's disease

Hum Mol Genet. 2014 Jun 1;23(11):3008-23. doi: 10.1093/hmg/ddu011. Epub 2014 Jan 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Apoptosis
  • Cytoskeleton / genetics
  • Cytoskeleton / metabolism
  • Disease Models, Animal
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Humans
  • Neurons / cytology
  • Neurons / metabolism
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / physiopathology
  • Protein Binding
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / toxicity
  • tau Proteins / genetics
  • tau Proteins / metabolism*
  • tau Proteins / toxicity

Substances

  • alpha-Synuclein
  • tau Proteins