Proteomic changes induced by harmine in human brain organoids reveal signaling pathways related to neuroprotection

Abstract

Harmine is a β-carboline found in Banisteriopsis caapi, a constituent of ayahuasca brew. Ayahuasca is consumed as a beverage in native Americans' sacred rituals and in religious ceremonies in Brazil. Throughout the years, the beneficial effects of ayahuasca to improve mental health and life quality have been reported, which propelled the investigation of its therapeutic potential to target neurological disorders such as depression and anxiety. Indeed, antidepressant effects of ayahuasca have been described, raising the question of which cellular mechanisms might underlie those effects. Previous animal studies describe potential neuroprotective mechanisms of harmine, including anti-inflammatory and antioxidant activities, and neurotrophin signaling activation. However, the cellular and molecular mechanisms modulated by harmine in human models remain less investigated. Here we analyzed the short-term changes in the proteome of human brain organoids treated with harmine using shotgun mass spectrometry. Harmine upregulates proteins related to synaptic vesicle cycle, cytoskeleton-dependent intracellular transport, cell cycle, glucose transporter-4 translocation, and neurotrophin signaling pathway. In addition, protein expression levels of Akt and phosphorylated CREB were increased after 24 hour-treatment. Our results shed light on the potential mechanisms that may underlie harmine-induced neuroprotective effects.

DYRK1A Regulates the Bidirectional Axonal Transport of APP in Human-Derived Neurons

“…Kim et al, 2016). Harmine treatment induced changes in different protein profiles (Karmirian et al, 2021); however, the main enriched biological processes we highlight were associated with cytoskeleton organization and microtubule-dependent transport. This is consistent with previous works that revealed the impact that DYRK1A has on neuronal morphogenesis through the regulation of cytoskeletal dynamics (Martinez de Lagran et al, 2012;Ori-McKenney et al, 2016).…”

“…Harmine modulates microtubule-based transport processes in human cerebral organoids DYRK1A has a myriad of phosphorylation targets; however, whether its inhibition impacts on cellular processes that regulate the metabolism of APP remains unknown. To search for novel intracellular pathways modulated by DYRK1A inhibition, we analyzed global changes in protein expression from a proteomic dataset obtained from harmine-treated human brain organoids at 7.5 mM for 24 h (Dakic et al, 2016) compared with control condition (DMSO) (Karmirian et al, 2021). Harmine, known as a potent DYRK1A inhibitor, was used to identify protein expression changes in human brain organoids following a pathway enrichment analysis of biological processes (Fig.…”

“…Bioinformatic analysis. The proteomic dataset of harmine-modified proteins available at Karmirian et al (2021) was uploaded to pathway enrichment analysis using Metascape database at a p value cutoff = 0.05, considering Gene Ontology Biological Process annotation (Zhou et al, 2019;Karmirian et al, 2021). Protein interaction networks were identified using the STRING database, considering medium and high confidence interactions.…”