Related Experiment Videos
Cyclin-dependent kinase 5 and mitogen-activated protein kinase in glial cytoplasmic inclusions in multiple system
S Nakamura1, Y Kawamoto, S Nakano
1Department of Neurology, Faculty of Medicine, Kyoto University, Japan.
Abstract:
Glial cytoplasmic inclusions (GCI) characteristically occur in the oligodendrocytes of patients with multiple system atrophy (MSA). However, the molecular mechanisms underlying GCI formation are unknown. To investigate whether these inclusions are related to proline-directed protein kinases that have been associated with neuronal inclusion bodies in some other neurodegenerative diseases, we immunohistochemically probed tissue samples from MSA brains with a panel of antibodies against cyclin-dependent kinases and mitogen-activated protein kinase. We unexpectedly detected cyclin-dependent kinase 5- (cdk5) and mitogen-activated protein kinase- (MAPK) immunoreactivities in GCI. We also found TAU1 immunoreactivity in GCI, and a strong expression of microtubule-associated protein (MAP) 2 immunoreactivity in oligodendrocytes of MSA brains. This immunoreactivity was not observed in the normal or neurological controls. The accumulated evidence suggest a close association between GCI and the microtubular cytoskeleton. Cdk5 phosphorylates tau and MAP2, and MAPK is capable of phosphorylating MAP2. The present results suggest that the aberrant or ectopic expression of cdk5 and MAPK causes abnormal phosphorylation of microtubular cytoskeletal proteins, thus leading to GCI formation in affected oligodendrocytes.
Insights
Glial cytoplasmic inclusions (GCI) in multiple system atrophy (MSA) may form due to abnormal phosphorylation of microtubule proteins by cyclin-dependent kinase 5 (cdk5) and mitogen-activated protein kinase (MAPK). This study reveals a potential molecular mechanism linking these kinases to GCI pathogenesis.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Glial cytoplasmic inclusions (GCI) are characteristic of multiple system atrophy (MSA).
- The molecular mechanisms driving GCI formation remain largely unknown.
- Proline-directed protein kinases are implicated in other neurodegenerative diseases.
Purpose of the Study:
- To investigate the potential role of proline-directed protein kinases in GCI formation in MSA.
- To examine the association between GCI and the microtubular cytoskeleton.
Main Methods:
- Immunohistochemical analysis of MSA brain tissue samples.
- Utilized antibodies against cyclin-dependent kinases (cdks) and mitogen-activated protein kinase (MAPK).
- Examined immunoreactivity for TAU1 and microtubule-associated protein (MAP) 2.
Main Results:
- Cyclin-dependent kinase 5 (cdk5) and mitogen-activated protein kinase (MAPK) immunoreactivities were detected within GCI.
- TAU1 and microtubule-associated protein (MAP) 2 immunoreactivities were found in oligodendrocytes of MSA brains, but not in controls.
- Evidence suggests a strong association between GCI and the microtubular cytoskeleton.
Conclusions:
- Aberrant expression of cdk5 and MAPK may lead to abnormal phosphorylation of microtubular cytoskeletal proteins.
- This abnormal phosphorylation is hypothesized to cause GCI formation in oligodendrocytes.
- The findings suggest a novel molecular pathway contributing to MSA neuropathology.