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Propionic acid induces dendritic spine loss by MAPK/ERK signaling and dysregulation of autophagic flux.

Molecular brain (2020-06-04)
Hyosun Choi, In Sik Kim, Ji Young Mun
RESUMEN

Propionic acid (PPA) is a short-chain fatty acid that is an important mediator of cellular metabolism. It is also a by-product of human gut enterobacteria and a common food preservative. A recent study found that rats administered with PPA showed autistic-like behaviors like restricted interest, impaired social behavior, and impaired reversal in a T-maze task. This study aimed to identify a link between PPA and autism phenotypes facilitated by signaling mechanisms in hippocampal neurons. Findings indicated autism-like pathogenesis associated with reduced dendritic spines in PPA-treated hippocampal neurons. To uncover the mechanisms underlying this loss, we evaluated autophagic flux, a functional readout of autophagy, using relevant biomedical markers. Results indicated that autophagic flux is impaired in PPA-treated hippocampal neurons. At a molecular level, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway was activated and autophagic activity was impaired. We also observed that a MAPK inhibitor rescued dendritic spine loss in PPA-treated hippocampal neurons. Taken together, these results suggest a previously unknown link between PPA and autophagy in spine formation regulation in hippocampal neurons via MAPK/ERK signaling. Our results indicate that MAPK/ERK signaling participates in autism pathogenesis by autophagy disruption affecting dendritic spine density. This study may help to elucidate other mechanisms underlying autism and provide a potential strategy for treating ASD-associated pathology.

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Sigma-Aldrich
Bafilomycin A1 from Streptomyces griseus, ≥90% (HPLC)
Sigma-Aldrich
Poli-D-lisina hydrobromide, mol wt 70,000-150,000
Sigma-Aldrich
Propionic acid, ACS reagent, ≥99.5%
Sigma-Aldrich
PD 98059, PD 98059, CAS 167869-21-8, is a cell-permeable, selective & reversible inhibitor of MAP Kinase Kinase (MEK). Inhibits MAP Kinase activation and subsequent phosphorylation of MAP Kinase substrates.