p75NTR modulation reverses oxidative stress and metabolic derangements in a cell model of Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease (AD), mainly affecting the elderly population with an incidence of 1-3%. It is characterized by motor symptoms closely linked to dopaminergic cell death in the Substantia nigra pars compacta. From a molecular standpoint, the deposition of Lewy bodies, namely protein aggregates particularly enriched with misfolded α-synuclein, is a typical hallmark of the disease. In addition, recent findings have highlighted cholesterol dysmetabolism as another common peculiarity of PD profoundly contributing to changes in membrane composition and integrity. Notably, p75 neurotrophin receptor (p75NTR) was found to be upregulated in the brains of post-mortem PD patients and associated with a reduction in the expression of pivotal neuroprotective effectors, strongly suggesting a role for this receptor in PD. Given its ability to favor both pro-survival and pro-apoptotic cascades, the synthesis of small p75NTR-binding molecules (i.e. LM11A-31) promoting cell viability over death was of particular interest in research. Hence, the aim of this study was to evaluate whether the pharmacological modulation of p75NTR by LM11A-31 provides neuroprotection in a rotenone-induced cellular model of PD. Our data showed that LM11A-31 promoted cell viability and reduced rotenone-dependent neuromorphological aberrations, as well as α-synuclein downregulation. We also observed that p75NTR modulation counteracted rotenone-dependent cholesterol alterations: specifically, LM11A-31 normalized free cholesterol content, as well as the expression of proteins involved in cholesterol uptake and trafficking. Furthermore, LM11A-31 reduced oxidative stress damage upon macromolecules by both boosting the expression of transcriptional regulators of the antioxidant response and reducing the expression of NADPH-oxidase (NOX) modulatory subunits. Even though further studies are required to better dissect the molecular mechanisms linking p75NTR to PD physiopathology, our data point to p75NTR modulation as a promising therapeutic avenue in PD treatment.