Targeted degradation of SNCA/α-synuclein aggregates in neurodegeneration using the AUTOTAC chemical platform

Abstract

Parkinson disease (PD) characterized by dopaminergic neuronal loss is caused by aggregation of misfolded SNCA/α-synuclein. We recently developed autophagy-targeting chimera (AUTOTAC), a targeted protein degradation (TPD) technology based on the macroautophagy/autophagy-lysosome pathway (ALP). In this study, we employed AUTOTAC to synthesize ATC161, a chimeric compound that adopts Anle138b as target-binding ligand (TBL) for SNCA aggregates. The autophagy-targeting ligand (ATL) of ATC161 was designed to allosterically activate the autophagy receptor SQSTSM1/p62 (sequestosome 1), a key step for targeting SNCA aggregates to the phagophore. The lysosomal degradation of SNCA aggregates by ATC161 acutely occurs at DC50 of 100-500 nM with no significant off-target degradation of monomeric SNCA. ATC161 protects cells from DNA and mitochondrial damage by SNCA aggregates. In PD model mice, oral administration of ATC161 decreases the level of SNCA aggregates and their propagation across brain regions, which mitigates glial inflammatory responses and improves muscle strength and locomotive activity. An Investigational New Drug (IND) was approved by the Korean Food and Drug Administration for a phase 1 clinical trial to treat PD, Alzheimer disease (AD), progressive supranuclear palsy (PSP), and amyotrophic lateral sclerosis (ALS). We suggest that AUTOTAC provides a platform for drug discovery in proteinopathies and other diseases.

Keywords: Autophagy-lysosome system; N-degron pathway; Parkinson’s disease; drug discovery; proteinopathies; targeted protein degradation.

Figure 1.

Graphical illustration of the autotac ATC161 in targeted degradation of SNCA/α-synuclein aggregates in PD. ATC161 employs Anle138b as the TBL that exhibits target selectivity to SNCA aggregates. In parallel, the ATL moiety of ATC161 binds the ZZ domain of SQSTM1, allosterically activating SQSTM1 to induce self-polymerization in the complex with SNCA aggregates. In addition, the exposed LIR domain of SQSTM1 enhances SQSTM1 interaction with LC3 on autophagic membranes and, thus, the delivery of SQSTM1-cargo complexes to phagophores. Following lysosomal degradation of SNCA aggregates, ATC161 is recycled back for subsequent rounds of degradation. The illustration was created with BioRender.com.