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bioRxiv · 10.1101/2024.12.25.630306

p75NTR modulation by LM11A-31 counteracts oxidative stress and cholesterol dysmetabolism in a rotenone-induced cell model of Parkinson's disease

Pensabene, D.·Martella, N.·Scavo, G.·Varone, M.·Bisesto, E.·Cavicchia, F.·Colardo, M.·Moreno, S.·Segatto, M.
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Abstract

Neurotrophins play pivotal roles in the development and proper functioning of the nervous system. The effects of these growth factors are mediated through the binding of high-affinity receptors, known as Trks, as well as the low-affinity receptor p75NTR. The latter has the capacity to induce complex signal pathways, as it favors both pro-survival and pro-apoptotic cascades depending on the physiopathological condition. Recent findings have indicated that p75NTR expression is increased in post-mortem Parkinsons disease (PD) brains, and this upregulation is associated with a significant reduction in neuroprotection. Given its double-edged sword nature, p75NTR has recently been identified as a promising therapeutic target to counteract neurodegenerative events. The present study aims to assess the neuroprotective effects of p75NTR modulation in a rotenone-induced neuronal model of PD. To this end, differentiated SH-SY5Y cells were exposed to rotenone to mimic the PD phenotype, and the small molecule LM11A-31 was used to modulate p75NTR activity. The main results revealed that LM11A-31 significantly mitigated the hallmarks of PD, including cell death, neuromorphological aberrations, and -synuclein accumulation. Pharmacological manipulation of p75NTR also reduced oxidative damage by increasing the expression of transcriptional factors that regulate the antioxidant response and by decreasing the expression of the pro-oxidant NADPH-oxidase modulatory subunits. Furthermore, LM11A-31 hampered cholesterol buildup induced by rotenone, normalizing the expression of proteins involved in cholesterol biosynthesis, uptake and intracellular trafficking. Taken together, these findings suggest that p75NTR modulation may represent a novel approach to counteracting PD abnormalities of redox and cholesterol metabolism.

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Pensabene, D., Martella, N., Scavo, G., Varone, M., Bisesto, E., Cavicchia, F., Colardo, M., Moreno, S., Segatto, M.. 2024-12-25. p75NTR modulation by LM11A-31 counteracts oxidative stress and cholesterol dysmetabolism in a rotenone-induced cell model of Parkinson's disease. https://doi.org/10.1101/2024.12.25.630306

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