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Neuronal loss and brain atrophy in mice lacking cathepsins B and L
Ute Felbor1, Benedikt Kessler, Walther Mothes
1Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. felbor@biozentrum.uni-wuerzburg.de
Abstract:
Cathepsins B and L are widely expressed cysteine proteases implicated in both intracellular proteolysis and extracellular matrix remodeling. However, specific roles remain to be validated in vivo. Here we show that combined deficiency of cathepsins B and L in mice is lethal during the second to fourth week of life. Cathepsin B(-/-)/L(-/-) mice reveal a degree of brain atrophy not previously seen in mice. This is because of massive apoptosis of select neurons in the cerebral cortex and the cerebellar Purkinje and granule cell layers. Neurodegeneration is accompanied by pronounced reactive astrocytosis and is preceded by an accumulation of ultrastructurally and biochemically unique lysosomal bodies in large cortical neurons and by axonal enlargements. Our data demonstrate a pivotal role for cathepsins B and L in maintenance of the central nervous system.
Insights
Combined deficiency of cathepsins B and L in mice is lethal, causing severe brain atrophy and neurodegeneration. These cysteine proteases are crucial for maintaining central nervous system integrity.
Area of Science:
- Biochemistry
- Neuroscience
- Molecular Biology
Background:
- Cathepsins B and L are cysteine proteases involved in protein degradation and tissue remodeling.
- Their specific in vivo functions, particularly in the central nervous system, require further elucidation.
Purpose of the Study:
- To investigate the in vivo necessity of cathepsins B and L for mammalian survival and central nervous system maintenance.
Main Methods:
- Generation of a double knockout mouse model lacking both cathepsin B and cathepsin L (Cathepsin B(-/-)/L(-/-)).
- Phenotypic analysis of knockout mice, including survival rates, brain morphology, neuronal apoptosis, and cellular pathology.
Main Results:
- Combined deficiency of cathepsins B and L resulted in early lethality (2-4 weeks of age).
- Cathepsin B(-/-)/L(-/-) mice exhibited significant brain atrophy, characterized by massive neuronal apoptosis in the cerebral cortex and cerebellum.
- Neurodegeneration was associated with reactive astrocytosis, axonal enlargements, and the accumulation of unique lysosomal bodies.
Conclusions:
- Cathepsins B and L play a critical and indispensable role in the maintenance and survival of the central nervous system.
- The study highlights a novel function of these proteases in preventing neurodegeneration.