Research

Neuroprotective and regenerative activity of γ-enolase as new therapeutic strategy in neuroinflammation-induced neurodegeneration

Code:

J1-70042

Range:

01. March 2026 - 28. February 2029

Range:

0.92 FTE

Leader:

Anja Pišlar

Field:

1.05 Natural sciences and mathematics/Biochemistry and molecular biology

Abstract:

Neurodegenerative disorders currently affect tens of millions of people worldwide. Despite significant research and a growing understanding of disease pathogenesis, only a handful of therapies are currently available and all of them provide only transient benefits. Thus, there is an urgent need to develop novel disease-modifying therapies to prevent the development or to slow down the progression of these debilitating disorders. Neurodegenerative diseases affect different regions of the brain, thus exhibiting distinctive and apparent characteristics at the phenotypic level, i.e., progressive loss of sensory-motor and cognitive functions. Out of many different types of neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most commonly occurring forms, where cholinergic and dopaminergic neurons, respectively, are the most frequently affected. Nevertheless, both neurodegenerative diseases are characterized by a unique pathomechanism, however, the involvement of certain processes in its etiology is common, such as neuroinflammation driven by glial activation. Microglia and astrocytes, upon activation, release pro-inflammatory cytokines and reactive oxygen species, contributing to neuronal damage. Persistent glial activation transforms protective responses into chronic inflammation, exacerbating disease progression and highlighting glia as potential therapeutic targets. In the context of both diseases, alterations in neurotrophic factors have been observed, which led to extensive efforts to elucidate their roles in pathology of AD and PD. Neurotrophic factors are imperative for recovery in neurodegenerative diseases. Their strong potential to elicit pro-survival, pro-differentiation and pro-functional responses in neurons, especially their ability to guide the axons in growth cones during regeneration make them promising candidates for treatment of a multitude of neurodegenerative disorders. Neurotrophic factor-like activity has been also demonstrated for a glycolytic enzyme γ-enolase, which promotes neuronal survival and differentiation through activation of the signal transduction pathways that are also triggered by neurotrophic factors. γ-Enolase-mediated neurotrophic activity is dependent on the proteolytic activity of the cysteine carboxypeptidase cathepsin X, which can cleave two C-terminal amino acids in γ-enolase, impairing neuronal survival and neuritogenesis. Thus, γ-enolase might not serve only as a neuronal marker, but could have a role in supporting glia cell functions due to its neurotrophic activity. The understanding of γ-enolase role and underlying molecular mechanism in modulating glia cells activation and inflammatory response is a focus of the proposed research project. Herein, we will investigate the neuroprotective and regenerative role of γ-enolase in neuroinflammation and neurodegeneration. By elucidating the expression patterns and functional role of γ-enolase in glial cells under neuroinflammatory conditions, we aim to uncover its contribution to glial cell activation and neuronal support. Finally, the proposed project seeks to develop and evaluate innovative tools to enhance γ-enolase-mediated neurotrophic activity, including synthetic peptides, mimicking γ-enolase neurotrophic activity, and cathepsin X inhibitors to increasing intact-active protein level of γ-enolase, for their therapeutic potential in advanced in vitro and in vivo models. Taken together, the results of proposed project will reveal the significance of γ-enolase neuroprotective and regenerative activity in neuroinflammation-induced neurodegeneration, which will foster the development of novel therapeutic strategies for treatment of neurodegenerative diseases such as enhancement of γ-enolase neurotrophic activity.