Treating LRRK2‐Related Parkinson's Disease by Inhibiting the mTOR Signaling Pathway to Restore Autophagy

Abstract Parkinson's disease (PD) is the most common chronic neurodegenerative disease and is characterized by motor dysfunctions. Pathogenic mutations in leucine‐rich repeat kinase 2 (LRRK2) are a major cause of the neurotoxicity that causes PD. As an inhibitor of LRRK2 activity, vitamin B12 (VB12) is a promising therapeutic option for PD and is shown to restore autophagy in PD models. However, the dependence on transporters and the extremely low brain tissue utilization of VB12 limit its therapeutic effects. Based on this, VB12‐loaded tetrahedral framework nucleic acid (TVC) is synthesized and its effectiveness in the model of PD induced with 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine is evaluated. TVC provides better recovery of autophagy than free VB12 did both in vivo and in vitro, leading to enhanced clearing of abnormal protein accumulations and restoration of PD motor symptoms. It is believed that TVC has broad therapeutic potential in the treatment of PD and similar neurodegenerative diseases.