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Mass Histology to Quantify Neurodegeneration in Drosophila
Published on: December 15, 2016
Neurodegeneration in a Drosophila model for the function of TMCC2, an amyloid protein precursor-interacting and
1Institute of Psychiatry and MRC Centre for Developmental Neurobiology, Kings College London, London, United Kingdom. hopkins.dementin@gmail.com
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.
Insights
Disrupting Dementin, a TMCC2 orthologue, causes Alzheimer's-like pathology in flies. Restoring Dementin in glial cells prevents neurodegeneration and rescues developmental defects.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- TMCC2 protein interacts differently with normal and Alzheimer's disease-risk forms of apolipoprotein E (apoE) and amyloid precursor protein (APP).
- Disrupted TMCC2 function is hypothesized to impact neurodegeneration.
Purpose of the Study:
- To investigate the role of TMCC2 in neurodegeneration using its Drosophila orthologue, Dementin.
- To determine if Dementin's function is linked to APP and neurodegenerative processes.
Main Methods:
- Investigated the Drosophila orthologue of TMCC2, named Dementin.
- Examined genetic interactions between Dementin, human APP, and Drosophila APPL.
- Utilized a hypomorphic lethal mutation (dmtn(1)) and RNA interference (RNAi) for Dementin.
- Assessed developmental and behavioral rescue experiments.
- Analyzed pathological features in adult flies with Dementin mutations.
Main Results:
- Dementin genetically interacts with both human APP and Drosophila APPL.
- Ectopic Dementin expression rescued developmental and behavioral defects caused by human APP.
- Dementin mutation or RNAi led to accumulation of APPL fragments.
- Dementin is crucial for normal brain development, with glial Dementin essential for the medulla neuropil.
- Rescue experiments showed Dementin's importance in both neurons and glia for survival.
- Flies with glial Dementin rescue exhibited Alzheimer's-like pathology, including abnormal APPL metabolites, synaptic issues, and neurodegeneration.
Conclusions:
- Dementin plays a critical role in neurodevelopment and preventing Alzheimer's-like pathology.
- Glial Dementin is essential for maintaining neuronal health and preventing neurodegeneration.
- Dementin's interaction with APPL highlights its significance in pathways relevant to Alzheimer's disease.
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