Retinoid X Receptor as a Novel Drug Target to Treat Neurological Disorders Associated with α- Synucleinopathies

Abstract

AbstractThe pathology of Parkinson’s Disease (PD) is multifaceted, with chronic neuroinflammation associated with glial cell activation standing out as a hallmark of PD pathophysiology. While a few treatments exist to interfere with inflammation, a breakthrough therapy based on innovative molecular mechanisms and targets is still awaited. The nuclear retinoid X receptor (RXR) is of particular interest for therapeutic intervention due to its ability to bind and activate permissive partners, NURR1 and PPARs, which have been shown to be dysfunctional in PD brains. Therefore, the goal of this study was to validate RXR-based therapy to slow down PD pathogenesis. Adult C57BL6 male mice were used in the study. PD-like pathology was triggered by co-delivery of AAV expressing α-Syn and PFF (AAV/PFF) to the substantia nigra pars compacta. The therapeutic potential of RXR activation was evaluated using AAV-mediated gene transport. Unbiased stereology, immunohistochemical analysis, LC/MS, and western blotting were employed to assess the therapeutic effect. At 8 weeks post-injection—elevated GFAP and Iba1 levels, associated with accumulated LB-like aggregates, pronounced loss of TH neuronal cells, and diminished dopamine (DA) levels—were observed in affected brains. Moreover, PPAR and NURR1 protein levels were also reduced in these brains. Conversely, RXR overexpression resulted in an increase in PPAR and NURR1 levels, a reduction in GFAP and Iba1 levels, and a decrease in the number and distribution of LB-like aggregates. These phenomena were also accompanied by the prevention of tyrosine hydroxylase (TH)+cell loss and the DA deficit in the treated brains. Therefore, our data provide direct evidence of the therapeutic potential of RXR-based therapy and highlight RXR as a novel drug target for PD.