Honokiol decreases alpha-synuclein mRNA levels and reveals novel targets for modulating alpha-synuclein expression.

Background: Intracytoplasmic inclusions comprised of aggregated alpha-synuclein (αsyn) represent a key histopathological feature of neurological disorders collectively termed "synucleinopathies," which includes Parkinson's disease (PD). Mutations and multiplications in the gene encoding αsyn cause familial forms of PD and a large body of evidence indicate a correlation between αsyn accumulation and disease. Decreasing αsyn expression is recognized as a valid target for PD therapeutics, with down-regulation of expression potentially attenuating downstream cascades of pathologic events. Here, we evaluated if Honokiol (HKL), a polyphenolic compound derived from magnolia tree bark with demonstrated neuroprotective properties, can modulate αsyn levels in multiple experimental models.

Methods: Human neuroglioma cells stably overexpressing αsyn, mouse primary neurons, and human iPSC-derived neurons were exposed to HKL and αsyn protein and messenger RNA levels were assessed. The effect of HKL on rotenone-induced overexpression of αsyn levels was further assessed and transcriptional profiling of mouse cortical neurons treated with HKL was performed to identify potential targets of HKL.

Results: We demonstrate that HKL can successfully reduce αsyn protein levels and expression in multiple models of PD with our data supporting a mechanism whereby HKL acts by post-transcriptional modulation of rather than modulating αsyn protein degradation. Transcriptional profiling of mouse cortical neurons treated with HKL identifies several differentially expressed genes (DEG) as potential targets to modulate expression.

Conclusion: This study supports a HKL-mediated downregulation of as a viable strategy to modify disease progression in PD and other synucleinopathies. HKL has potential as a powerful tool for investigating gene modulation and its downstream effects.