Lack of neuroprotection after systemic administration of the soluble TNF inhibitor XPro1595 in an rAAV6-α-Syn + PFFs-induced rat model for Parkinson's disease

• Autores: Fredlund, Filip; Fryklund, Claes; Trujeque-Ramos, Olivia; Staley, Hannah A.; Pardo, Joaquin; Luk, Kelvin C.; Tansey, Malú G.; Swanberg, Maria
• Año de publicación: 2025
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: TNF; Enfermedad de Parkinson; Neurodegeneración; Neuroinflamación; alpha synucleina; Fibras pre formadas (PFF); CIITA
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration, α-Synuclein (α-Syn)pathology, and inflammation. Microglia in the substantia nigra pars compacta (SNpc) upregulatemajor histocompatibility complex class II (MHCII), and variants in genes encoding MHCII affect PDrisk. Additionally, elevated TNF levels and α-Syn-reactive T cells in circulation suggest a strong linkbetween innate and adaptive immune responses in PD. We have previously reported that reducedlevels of the class II transactivator, the master regulator of MHCII expression, increases susceptibilityto α-Syn-induced PD-like pathology in rats and are associated with higher serum levels of solubleTNF (sTNF). Here, we demonstrate that inhibiting sTNF with a dominant-negative TNF variant,XPro1595, known to be neuroprotective in endotoxin- and toxin-induced neurodegeneration models,fails to protect against robust α-Syn-induced PD-like pathology in rats. We used a model combiningrAAV-mediated α-Syn overexpression in SNpc with striatal injection of α-Syn preformed fibrils twoweeks later. Systemic XPro1595 treatment was initiated one-week post-rAAV-α-Syn. We observedup to 70% loss of striatal dopaminergic fibers without treatment, and no protective effects ondopaminergic neurodegeneration after XPro1595 administration. Pathological α-Syn levels as well asmicroglial and astrocytic activation were not reduced in SNpc or striatum following XPro1595treatment. An increase in IL-6 and IL-1β levels in CSF was observed in rats treated with XPro1595,possibly explaining a lack of protective effects following treatment. Our results highlight the need todetermine the importance of timing of treatment initiation, which is crucial for future applications ofsTNF therapies in PD patients.
Fil: Fredlund, Filip. Department Of Experimental Medical Science ; Faculty Of Medicine ; Lund University;
Fil: Fryklund, Claes. University of Florida; Estados Unidos
Fil: Trujeque-Ramos, Olivia. Department Of Experimental Medical Science ; Faculty Of Medicine ; Lund University;
Fil: Staley, Hannah A.. University of Florida; Estados Unidos
Fil: Pardo, Joaquin. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Luk, Kelvin C.. University of Pennsylvania; Estados Unidos
Fil: Tansey, Malú G.. University of Florida; Estados Unidos
Fil: Swanberg, Maria. Department Of Experimental Medical Science ; Faculty Of Medicine ; Lund University;