CNS-11g reduces α-synuclein pathology and restores motor function in a Parkinson’s model

Background Fibrillar aggregates of α-synuclein (α-syn) drive progressive neurodegeneration in Parkinson’s disease (PD) and other synucleinopathies. Despite their central role, no approved therapies directly target toxic α-syn species. Structure-based methods identify small molecules, including CNS-11g, that reduce seeding and disassemble fibrils. However, the in vivo efficacy of CNS-11g in a mammalian model of PD is unknown. Methods Aged (23–25 month-old) M83 mice (A53T α-syn) received CNS-11g (5 mg/kg, for 6 weeks; n = 20) or vehicle (n = 21). The final group sizes were CNS-11g: n = 19; vehicle: n = 15. After rotarod testing, brains were collected for biochemical and histological analyses. Results CNS-11g achieved brain concentrations of 100 nM to 1.8 µM, sufficient to inhibit the seeding of patient-derived α-syn fibrils in vitro. CNS-11g treatment significantly increased survival probability from 82% to 98%, attenuated weight loss by 32%, and improved motor coordination by 39% (rotarod latency to fall). CNS-11g reduced the percentage area of pS129-positive α-syn immunostaining in the pons by 8.2-fold and reduced brainstem SDS-stable, high-molecular-weight (>250 kDa) soluble α-syn aggregates by 30%, without affecting detergent-insoluble pS129 α-syn. In brainstem lysates, CNS-11g increased SNAP25/α-tubulin by 82% and restored the correlation between SNAP25 and VAMP2 (slope = 0.84). CNS-11g corrected a 23.2% transgene-dependent loss of dopaminergic neurons in the substantia nigra (#cells/mm ² ). It also corrected the transgene-dependent loss of the LC3β-positive area by 40.2%, yet the LC3β staining intensity increased by 8.7%. There were notable region-specific effects on neuroinflammation. CNS-11g fully corrected 54% of the transgene-associated increase in astroglial process area in the pons. CNS-11g increased microglial soma size by 35% relative to vehicle in M83 mice. CNS-11g produced similar microglial changes in the corpus callosum, which was consistent with enhanced clearance following α-syn fibril inhibition. Conclusions Late-stage intervention with CNS-11g, mitigated cachexia, early death, and motor deficits while reducing pathological aggregation and autophagic and neuroinflammatory dysregulation. These findings establish proof-of-concept for CNS-11g as a disease-modifying strategy in synucleinopathies.