MODULATION OF NEUROTROPHIC SIGNALING PATHWAYS IN NEURONAL DYSFUNCTION ASSOCIATED WITH PARKINSON’S DISEASE

Neurotrophic signaling pathways play a crucial role in the regulation of neuronal survival, plasticity, stress responses and their dysregulation have been implicated in the pathogenesis of Parkinson’s disease (PD). Among these pathways, the p75 neurotrophin receptor (p75NTR) has emerged as a context-dependent regulator of neuronal fate, capable of engaging both degenerative and protective mechanisms depending on its molecular interactions. Although the modulation of p75NTR has been proposed as a valuable therapeutic avenue for various neurodegenerations, its role in PD remains underexplored. In this context, we investigated the neuroprotective effects of p75NTR modulation by the small molecule LM11A-31 in a rotenone-induced neuronal model of PD. Our data indicated that the modulation of p75NTR rescued typical parkinsonian hallmarks such as abnormal α-synuclein expression and neuromorphological aberrations, while also contributing to redox homeostasis. Notably, LM11A-31 ameliorated mitochondrial network homeostasis and favored the downregulation of NADPH oxidase (NOX) subunits, mitigating the production of reactive oxygen species (ROS). In parallel, p75NTR modulation reduced lysosomal cholesterol engulfment promoting its redistribution within subcellular membranes. The fact that LM11A-31 successfully entered phase IIa Clinical Trial for Alzheimer’s Disease underlines the translational potential of p75NTR targeting as valuable therapeutic avenue also against PD.