The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches

Lysosomes are ubiquitous organelles with a fundamental role in maintaining cellular homeostasis by mediating degradation and recycling processes. Cathepsins are the most abundant lysosomal hydrolyses and are responsible for the bulk degradation of various substrates. A correct autophagic function is essential for neuronal survival, as most neurons are post-mitotic and thus susceptible to accumulate cellular components. Increasing evidence suggests a crucial role of the lysosome in neurodegeneration as a key regulator of aggregation-prone and disease associated proteins, such as alpha-synuclein, beta-amyloid and huntingtin. Particularly, alterations in lysosomal cathepsins CTSD, CTSB and CTSL can contribute to the pathogenesis of neurodegenerative diseases as seen for neuronal ceroid lipofuscinosis, synucleinopathies (Parkinson's disease, Dementia with Lewy Body and Multiple System Atrophy) as well as Alzheimer's and Huntington's disease. In this review, we provide an overview of recent evidence implicating CTSD, CTSB and CTSL in neurodegeneration, with a special focus on the role of these enzymes in alpha-synuclein metabolism. In addition, we summarize the potential role of lysosomal cathepsins as clinical biomarkers in neurodegenerative diseases and discuss potential therapeutic approaches by targeting lysosomal function.

Automated summary

Lysosomes play a crucial role in maintaining cellular homeostasis, and alterations in lysosomal cathepsins CTSD, CTSB, and CTSL are implicated in the pathogenesis of various neurodegenerative diseases. This review provides an overview of the role of these enzymes in neurodegeneration, particularly in alpha-synuclein metabolism, and discusses their potential as clinical biomarkers and therapeutic targets for neurodegenerative diseases.