Targeting Cathepsins in Neurodegeneration: Biochemical Advances

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Cathepsins are lysosomal proteases vital for maintaining neuronal proteostasis by clearing misfolded and aggregated proteins.
• Dysregulation of cathepsins is linked to neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's, characterized by toxic protein buildup.

Purpose of the Study:

• To review the roles of cathepsins in cellular stress pathways relevant to neurodegeneration.
• To evaluate the therapeutic potential of targeting cathepsins for neurological disorders.

Main Methods:

• Comprehensive literature review of in vitro and in vivo studies on cathepsin function, inhibition, and modulation.
• Analysis of mechanistic insights and pharmacological strategies targeting cathepsins.
• Assessment of challenges in translating preclinical findings to clinical applications.

Main Results:

• Cathepsins exhibit a dual role, aiding neuronal health via aggregate degradation but potentially worsening stress when dysregulated.
• Cathepsins influence autophagy, apoptosis, and neuroinflammation, acting both intracellularly and extracellularly.
• Clinical translation is impeded by poor inhibitor selectivity, limited brain penetration, and model variability.

Conclusions:

• Targeting cathepsins is a promising therapeutic strategy for neurodegenerative and neuropsychiatric disorders.
• Significant hurdles remain, including enhancing drug specificity and brain delivery.
• Future research requires standardized models to improve prediction of clinical outcomes.