Cells of the central nervous system require highly regulated signaling pathways for development and function, with neurotrophic factors playing a key role in these processes. Enzyme γ-enolase, in addition to its glycolytic function, acts as a neurotrophic factor whose activity is regulated by the cysteine peptidase cathepsin X through C-terminal cleavage. The present doctoral thesis investigates the role of γ-enolase and its regulation in central nervous system cells, focusing on their relevance in neuronal differentiation, survival, and inflammation-induced neurodegeneration.
Our findings demonstrate that during neuronal differentiation, particularly toward a cholinergic phenotype, levels of active γ-enolase increase in association with enhanced neurite extension, reduced cellular proliferation, and upregulated expression of neuronal maturation markers. Inhibition of cathepsin X further elevated γ-enolase active form and facilitated neuronal differentiation. In cellular models of Alzheimer’s and Parkinson’s diseases, pathological agents such as amyloid β-peptide and 6-hydroxydopamine reduced active form of γ-enolase levels, compromising its neurotrophic function. Conversely, treatment with a γ-enolase–derived peptide that mimics its neurotrophic activity, or with a cathepsin X inhibitor that preserves active γ-enolase, maintained cytoskeletal integrity and improved neuronal survival. In glial cells, cathepsin X inhibition increased the levels of active form of γ-enolase, enhancing cell viability and exerting neuroprotective effects. Specifically, it reduced inflammatory activation in microglia and promoted oligodendrocyte differentiation and myelination. Moreover, secreted γ-enolase from glial cells supported neuronal survival under inflammatory conditions. In an in vivo model of experimental autoimmune encephalomyelitis, expression of active γ-enolase increased at peak disease stages, together with regeneration markers and cathepsin X activity.
These findings elucidate the role of γ-enolase across distinct cell types of central nervous system and highlight its involvement in inflammatory and degenerative mechanisms, thereby providing a basis for therapeutic approaches in neurodegeneration. Altogether, cathepsin X inhibitors and γ-enolase mimetic peptides emerge as promising strategies for neurodegenerative diseases.
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