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Reduced sodium channel Na(v)1.1 levels in BACE1-null mice
Doo Yeon Kim1, Manuel T Gersbacher1, Perrine Inquimbert2
1From the Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 and.
The Journal of Biological Chemistry
|December 31, 2010
Summary
The Alzheimer BACE1 enzyme regulates sodium channel metabolism. BACE1-null mice show decreased voltage-gated sodium channel Na(v)1.1 levels, impacting neuronal function and potentially causing seizures.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- The BACE1 enzyme's role in cleaving substrates is not fully understood.
- Elevated BACE1 activity has been linked to altered voltage-gated sodium channel Na(v)1.1 density and neuronal function.
- Investigating BACE1's impact on sodium channel metabolism is crucial for understanding neuronal excitability.
Purpose of the Study:
- To analyze physiological changes in sodium channel metabolism in BACE1-null mice.
- To elucidate the mechanism by which BACE1 regulates sodium channel levels.
- To assess the potential consequences of BACE1 activity on neuronal function and excitability.
Main Methods:
- Analysis of sodium channel α-subunit levels in brains of BACE1-null and wild-type mice.
- Surface biotinylation studies in hippocampal slices.
- Measurement of Na(v)β(2) processing and Na(v)1.1 mRNA levels.
Main Results:
- BACE1-null mice exhibited significantly decreased Na(v)1.1 protein levels in the brain and hippocampus.
- Levels of Na(v)1.2 and Na(v)1.6 α-subunits were also reduced in young BACE1-null mice.
- Surface Na(v)1.1 levels decreased, while surface Na(v)1.2 levels increased in the hippocampus of BACE1-null mice.
Conclusions:
- Endogenous BACE1 activity is essential for regulating total and surface levels of voltage-gated sodium channels in the brain.
- BACE1 may regulate Na(v)1.1 mRNA levels via Na(v)β(2) cleavage, impacting neuronal excitability.
- Therapeutic BACE1 inhibition in Alzheimer's disease could alter Na(v)1 metabolism and neuronal function.
