title: Neurodegeneration in a Drosophila model for the function of TMCC2, an amyloid protein precursor-interacting and apolipoprotein E-binding protein.
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.
authors: Institute of Psychiatry and MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom. hopkins.dementin@gmail.com
authors: Paul C R
authors: PC
authors: Hopkins
mesh_terms: D000483:Alleles; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002352:Carrier Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D002490:Central Nervous System / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D004843:Epistasis, Genetic; D020869:Gene Expression Profiling; D023061:Gene Order; D008297:Male; D005810:Multigene Family; D010802:Phylogeny; D011485:Protein Binding; D034622:RNA Interference
chemical_list: D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D002352:Carrier Proteins; C582651:Dmtn protein, Drosophila; D029721:Drosophila Proteins