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MARKing tau for tangles and toxicity
1Cellzome AG, Meyerhofstrasse 1, D-69117 Heidelberg, Germany. gerard.drewes@cellzome.com
Trends in Biochemical Sciences
|September 29, 2004
Summary
In Alzheimer's disease, abnormal tau protein phosphorylation disrupts microtubule function and leads to toxic neurofibrillary tangles. These early phosphorylation events compromise neuronal integrity, even before tangle formation.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Tau proteins are crucial for microtubule stability in healthy neurons.
- In Alzheimer's disease, tau proteins become hyperphosphorylated and form neurofibrillary tangles (NFTs).
- This hyperphosphorylation detaches tau from microtubules, potentially impairing axonal function and generating toxic tau peptides.
Purpose of the Study:
- To re-evaluate the mechanisms of tau phosphorylation in neurofibrillar pathology.
- To understand the sequential role of kinases in initiating tau aggregation.
- To identify early pathological events contributing to neuronal dysfunction in Alzheimer's disease.
Main Methods:
- Biochemical analyses of tau phosphorylation.
- Studies utilizing animal models of neurofibrillar pathology.
Main Results:
- Phosphorylation by MARK primes tau for subsequent hyperphosphorylation by GSK-3 and Cdk5.
- This sequential phosphorylation initiates tau aggregation into filaments and tangles.
- Neuronal toxicity is evident early in the process, preceding or concurrent with tangle formation.
Conclusions:
- The study elucidates a specific kinase cascade (MARK, GSK-3, Cdk5) driving tau pathology.
- Early tau phosphorylation events, not just mature tangles, contribute significantly to neuronal damage.
- Findings offer insights into potential therapeutic targets for Alzheimer's disease by intervening in early tau phosphorylation.