Employing the target protein degradation strategy to treat neurodegenerative disease can be revolutionary as protein aggregates are among the major pathologies and many attempts to modulate these diseases with conventional small-molecule drugs have not been successful. Significant effort has already been made to target neurodegenerative disease related proteins with either peptide-based or small molecular PROTAC degraders . However, achieving favorable PK profiles with oral bioavailability and BBB penetration have been the major obstacles for central nervous system (CNS)-targeted PROTACs. Amongst the only successes reported to date, Wang et al. developed a tautargeting PROTAC (C004019) that can penetrate the BBB after subcutaneous injection and induce tau protein degradation in the brain . Herein, we disclose the identification of a LRRK2-targeting PROTAC that exhibits remarkable oral bioavailability and BBB penetration. Both CC004019 and XL01126 are VHL-based PROTACs with multiple violations of Ro5 and/or RoCNS. Their capability of penetrating the BBB challenges the Ro5-and RoCNS-based pre-conceptions and dogma and has expanded the chemical space of CNS targeting drugs. Although BBB penetrant, XL01126 showed low concentration in the brain and in CSF, with low brain-to-plasma ratio (< 0.035). Nevertheless, given the substoichiometric/catalytic mechanism of action, which is different from the occupancy-driven mechanism of inhibitors, PROTACs may achieve target protein degradation in the targeted tissue even with low exposure.