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Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer-like state
G Drewes1, B Lichtenberg-Kraag, F Döring
1Max-Planck-Unit for Structural Molecular Biology, Hamburg, Germany.
Abstract:
The microtubule-associated protein tau is a major component of the paired helical filaments (PHFs) observed in Alzheimer's disease brains. The pathological tau is distinguished from normal tau by its state of phosphorylation, higher apparent M(r) and reaction with certain antibodies. However, the protein kinase(s) have not been characterized so far. Here we describe a protein kinase from brain which specifically induces the Alzheimer-like state in tau protein. The 42 kDa protein belongs to the family of mitogen activated protein kinases (MAPKs) and is activated by tyrosine phosphorylation. It is capable of phosphorylating Ser-Pro and Thr-Pro motifs in tau protein (approximately 14-16 P1 per tau molecule). By contrast, other proline directed Ser/Thr kinases such as p34(cdc2) combined with cyclin A or B have only minor effects on tau phosphorylation. We propose that MAP kinase is abnormally active in Alzheimer brain tissue, or that the corresponding phosphatases are abnormally passive, due to a breakdown of the normal regulatory mechanisms.
Insights
Researchers identified a specific brain protein kinase, a type of mitogen-activated protein kinase (MAPK), that causes tau protein to adopt an Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Microtubule-associated protein tau is a key component of paired helical filaments (PHFs) in Alzheimer's disease (AD) brains.
- Pathological tau differs from normal tau due to phosphorylation, higher molecular weight, and antibody reactivity.
- The specific protein kinases responsible for tau's pathological phosphorylation in AD remain largely uncharacterized.
Purpose of the Study:
- To identify and characterize the protein kinase responsible for inducing the Alzheimer's-like state in tau protein.
- To investigate the role of this kinase in the pathological tau phosphorylation observed in Alzheimer's disease.
Main Methods:
- Isolation and characterization of a novel brain protein kinase.
- Assaying the kinase's ability to phosphorylate tau protein, specifically targeting Ser-Pro and Thr-Pro motifs.
- Comparison of the identified kinase's activity with other proline-directed Ser/Thr kinases like p34(cdc2)/cyclin A/B.
Main Results:
- A 42 kDa protein kinase, belonging to the mitogen-activated protein kinase (MAPK) family, was identified.
- This MAPK specifically phosphorylates tau protein at Ser-Pro and Thr-Pro motifs, adding approximately 14-16 phosphate groups per tau molecule.
- Other proline-directed kinases showed minimal effects on tau phosphorylation compared to the identified MAPK.
Conclusions:
- Mitogen-activated protein kinase (MAPK) is identified as a key enzyme inducing the Alzheimer's-like phosphorylation state in tau protein.
- Abnormal MAPK activity or reduced phosphatase activity in Alzheimer's disease brains may result from a breakdown in regulatory mechanisms.
- This finding provides a potential target for understanding and treating Alzheimer's disease pathogenesis related to tau pathology.