Approaching α-synuclein misfolding through gut microbiome; strategies for the management of neurological conditions

Protein misfolding plays a fundamental role in the onset of numerous cellular pathologies. Among these, alpha-synuclein (α-syn) misfolding is central to the pathogenesis of both neurodevelopmental and neurodegenerative disorders. The SH-SY5Y human neuroblastoma cell line serves as a valuable model to recapitulate α-syn misfolding observed in vivo, offering insight into various therapeutic strategies. Despite intensive research, no intervention has yet proven to be consistently safe, effective, and reproducible in preventing α-syn misfolding. This review explores the mechanistic underpinnings of α-syn pathology including endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and gut microbiome dysbiosis and introduces exopolysaccharide β-glucans as promising, multifaceted therapeutic agents. Especially focussing on those 1-3,1-6 β-glucans from the polyextremotolerant yeast Aureobasidium pullulans, which have shown potential in modulating the gut-brain axis, reducing inflammation, promoting epigenetic stability, and facilitating the clearance of aggregated α-syn. Their broad-spectrum biological response-modifying activities could form the basis for novel adjunctive therapies aimed at neurodegenerative and neurodevelopmental conditions.