Cysteine cathepsins in neurological disorders

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Increased proteolytic activity, particularly involving cathepsins (lysosomal cysteine proteases), is a key feature of neurodegenerative diseases.
• A disturbed balance in cathepsin activity is an early event in brain aging and age-related disorders.
• Cathepsin leakage from lysosomes and microglial activation contribute to neuronal death.

Purpose of the Study:

• To investigate the role of cathepsins in neurodegeneration.
• To explore the failure of endogenous inhibitors (cystatins) in neurodegenerative conditions.
• To assess the therapeutic potential of exogenous cathepsin inhibitors for neurological disorders.

Main Methods:

• Analysis of cathepsin expression and activity in neurodegeneration models.
• Investigation of lysosomal membrane permeability and its role in cathepsin release.
• Evaluation of cystatin function in the context of neurodegeneration.
• Assessment of synthetic cathepsin inhibitors as potential therapeutic agents.

Main Results:

• Elevated cathepsin expression and activity are consistently observed during central nervous system degeneration.
• Lysosomal membrane permeability and subsequent cathepsin leakage exacerbate neurodegeneration.
• Activated microglia-expressed cathepsins play a critical role in inflammation-induced neuronal death.
• Endogenous cystatins appear insufficient to control cathepsin activity in neurodegenerative processes.

Conclusions:

• Cathepsins are significant contributors to neurodegeneration and brain aging.
• Dysfunctional endogenous inhibition by cystatins highlights a therapeutic gap.
• Exogenous synthetic inhibitors represent a promising avenue for treating neurological disorders by modulating cathepsin activity.