Neurodegeneration in a Drosophila model for the function of TMCC2, an amyloid protein precursor-interacting and apolipoprotein E-binding protein

PLoS One. 2013;8(2):e55810. doi: 10.1371/journal.pone.0055810. Epub 2013 Feb 7.

Abstract

We previously identified TMCC2 as a protein that interacted differentially with normal versus Alzheimer's disease-risk forms of both apolipoprotein E (apoE) and the amyloid protein precursor (APP). We hypothesized that disrupted function of TMCC2 would affect neurodegeneration. To test this hypothesis, we investigated the Drosophila orthologue of TMCC2, that we have named Dementin. We showed that Dementin interacts genetically both with human APP and its Drosophila orthologue, the APP-like protein (APPL). Ectopic expression of Dementin in Drosophila rescued developmental and behavioral defects caused by expression of human APP. Both a hypomorphic lethal mutation in the dementin gene (dmtn(1)) and RNAi for Dementin caused the accumulation of fragments derived from APPL. We found that Dementin was required for normal development of the brain, and that glial Dementin was required for development of the Drosophila medulla neuropil. Expression of wild-type Dementin in either the neurons or glia of dmtn(1) flies rescued developmental lethality. Adult dmtn(1) flies rescued by expression of wild-type Dementin in glia, i.e. whose neurons expressed only dmtn(1), showed pathological features resembling early onset Alzheimer's disease, accumulation of abnormal APPL metabolites, synaptic pathology, mis-localized microtubule-binding proteins, neurodegeneration, and early death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Apolipoproteins E / genetics
  • Apolipoproteins E / metabolism*
  • Brain / embryology
  • Brain / metabolism
  • Carrier Proteins / classification
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Central Nervous System / metabolism
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / classification
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Epistasis, Genetic
  • Gene Expression Profiling
  • Gene Order
  • Male
  • Multigene Family
  • Phylogeny
  • Protein Binding
  • RNA Interference

Substances

  • Amyloid beta-Protein Precursor
  • Apolipoproteins E
  • Carrier Proteins
  • Dmtn protein, Drosophila
  • Drosophila Proteins

Grant support

The work was funded by grants from the Alzheimer's Society (alzheimers.org.uk) and Alzheimer's Research UK (www.alzheimersresearchuk.org) awarded to PCRH. The author thanks benefactor JAH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.