AUTHOR=Fagen Sara J. , Burgess Jeremy D. , Lim Melina J. , Amerna Danilyn , Kaya Zeynep B. , Faroqi Ayman H. , Perisetla Priyanka , DeMeo Natasha N. , Stojkovska Iva , Quiriconi Drew J. , Mazzulli Joseph R. , Delenclos Marion , Boschen Suelen L. , McLean Pamela J. 

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

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=15

YEAR=2023

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2023.1179086

DOI=10.3389/fnagi.2023.1179086

ISSN=1663-4365

ABSTRACT=<sec><title>Background</title><p>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 <italic>SNCA</italic> 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 <italic>SNCA</italic> 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.</p></sec><sec><title>Methods</title><p>Human neuroglioma cells stably overexpressing αsyn, mouse primary neurons, and human iPSC-derived neurons were exposed to HKL and αsyn protein and <italic>SNCA</italic> 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.</p></sec><sec><title>Results</title><p>We demonstrate that HKL can successfully reduce αsyn protein levels and <italic>SNCA</italic> expression in multiple <italic>in vitro</italic> models of PD with our data supporting a mechanism whereby HKL acts by post-transcriptional modulation of <italic>SNCA</italic> 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 <italic>SNCA</italic> expression.</p></sec><sec><title>Conclusion</title><p>This study supports a HKL-mediated downregulation of <italic>SNCA</italic> as a viable strategy to modify disease progression in PD and other synucleinopathies. HKL has potential as a powerful tool for investigating <italic>SNCA</italic> gene modulation and its downstream effects.</p></sec>