Cordycepin promotes autophagic degradation of α-synuclein via CacyBP/SIP activation for ameliorating olfactory dysfunction against Parkinson's disease

Olfactory dysfunction is one of the earliest non-motor symptoms of Parkinson's disease (PD), accompanied by abnormal α-synuclein aggregation in the olfactory bulb (OB). We previously reported that Cordycepin (Cor), a potential anti-inflammatory and anti-oxidative adenosine derivative, has emerged as an attractive candidate for PD treatment. However, existing investigations have predominantly focused on the amelioration of motor symptoms rather than modulating the disease course from prodromal stage. This study aimed to evaluate if Cor exerts a disease-modifying effect at the prodromal stage prior to the onset of motor deficits in eight-week-old male C57BL/6 mice exposed to rotenone. Our results showed that Cor administration significantly attenuated olfactory dysfunction and delayed the onset of motor impairments. This therapeutic effect was concomitant with pathological α-synuclein aggregates degradation in OB. RNA sequencing analyses revealed that Autophagy-lysosomal pathway (ALP) in OB may be associated with the neuroprotective actions of Cor in PD. Furthermore, Cor significantly stabilized Calcyclin-binding protein/Siah1-interacting protein (CacyBP/SIP) via inhibiting its ubiquitin-proteasome degradation in rotenone-treated SH-SY5Y cells. This stabilization suppressed NLRP3 inflammasome activation and subsequently enhanced autophagosome-lysosome fusion, culminating in the autophagic degradation of α-synuclein. Notably, blockade of CacyBP/SIP abrogated the neuroprotective effects of Cor against rotenone-induced olfactory impairment. Collectively, these findings suggest CacyBP/SIP-NLRP3-α-synuclein axis may serve as a key target of Cor in the early treatment of PD, which provides novel insights into the mechanisms for the anti-PD effect of Cor.