Shiitake-derived lentinan prevents α-synuclein aggregation, disassembles amyloid aggregates, and protects dopaminergic neurons

Parkinson’s disease (PD) is the second largest degenerative disease of central nervous system around the world. α-Synuclein (α-syn) is the main component of Lewy body amyloid deposits in the brain of PD patients and associated with the pathogenesis of PD. α-Syn aggregates can induce neuron death and cause irreversible neurological damage. Therefore, the inhibition of α-syn aggregation and removal of preformed amyloid fibers are important strategies for the prevention and treatment of PD. However, there is still a lack of potent inhibitors to interfere with α-syn aggregation. In this work, we demonstrate that lentinan (LNT), a natural polysaccharide extracted from the fruit body of Lentinula edodes, can potently prevent α-syn aggregation, disassemble preformed amyloid aggregates, and suppress α-syn-mediated cell toxicity and reactive oxygen species generation. Interestingly, we also find that the molecular weight of the polysaccharide impacts the inhibitory effect of LNT. Further in vivo investigation demonstrates that LNT significantly inhibits the accumulation of α-syn in nematodes C. elegans, relieves the symptoms of PD nematode motility disorders, and effectively protects dopaminergic neurons from C. elegans PD models. To the best of our knowledge, this is the first time to report that LNT can modulate α-syn aggregation in vitro and in vivo, which will provide new insights for designing and developing potential agents for PD treatment.