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G protein-mediated neuronal DNA fragmentation induced by familial Alzheimer's disease-associated mutants of APP
T Yamatsuji1, T Matsui, T Okamoto
1Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Abstract:
Missense mutations in the 695-amino acid form of the amyloid precursor protein (APP695) cosegregate with disease phenotype in families with dominantly inherited Alzheimer's disease. These mutations convert valine at position 642 to isoleucine, phenylalanine, or glycine. Expression of these mutant proteins, but not of normal APP695, was shown to induce nucleosomal DNA fragmentation in neuronal cells. Induction of DNA fragmentation required the cytoplasmic domain of the mutants and appeared to be mediated by heterotrimeric guanosine triphosphate-binding proteins (G proteins).
Insights
Missense mutations in amyloid precursor protein (APP695) are linked to inherited Alzheimer's disease. These mutations trigger DNA fragmentation in neuronal cells, suggesting a novel disease mechanism.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Dominantly inherited Alzheimer's disease is associated with mutations in the amyloid precursor protein (APP).
- Specific missense mutations in APP695 (e.g., V642I, V642F, V642G) have been identified in affected families.
Purpose of the Study:
- To investigate the functional consequences of APP695 missense mutations.
- To determine if mutant APP proteins induce cellular damage relevant to Alzheimer's pathogenesis.
Main Methods:
- Expression of normal and mutant APP695 in neuronal cells.
- Assessment of nucleosomal DNA fragmentation as a marker of apoptosis.
- Analysis of the role of the cytoplasmic domain and G proteins in the observed effects.
Main Results:
- Expression of mutant APP695, but not wild-type APP695, induced nucleosomal DNA fragmentation in neuronal cells.
- The induction of DNA fragmentation was dependent on the cytoplasmic domain of the mutant APP.
- Evidence suggests mediation of DNA fragmentation by heterotrimeric guanosine triphosphate-binding proteins (G proteins).
Conclusions:
- Missense mutations in APP695 can directly induce neuronal cell death via DNA fragmentation.
- The cytoplasmic domain of mutant APP and G protein signaling are critical components of this pathogenic pathway.
- These findings provide new insights into the molecular mechanisms underlying familial Alzheimer's disease.