Ulvan Polysaccharides And Oligosaccharides Inhibit α-synuclein Fibrillogenesis And Reduce Amyloid Cytotoxicity

Parkinson disease(PD)is one of the most common neurodegenerative diseases,affecting the normal lives of millions of patients worldwide.One of the pathogenesis of PD is that α-synuclein(α-syn)aggregates into amyloid fibers,thereby disrupting cellular homeostasis and producing neurotoxic substances.Therefore,the development of safe and efficient inhibitors that interfere with α-syn aggregation has become an important strategy in the treatment of PD.In this study,the inhibitory effects of ulvan polysaccharides and oligosaccharides on α-syn aggregation were systematically studied using biophysics,biochemistry,cell biology and nematode experiments.Thioflavin T(Th T)fluorescence spectroscopy results showed that ulvan polysaccharides and oligosaccharides significantly inhibited α-syn fibrillogenesis in a dose-dependent manner.For example,0.5,1 and 2 mg/m L ulvan polysaccharides reduced Th T fluorescence intensity to 57.56%,48.13% and 27.87%,respectively.The fluorescence intensity of Th T decreased to 53.11%,20.37% and 0.20% under 0.25,0.5 and 1 mg/m L with ulvan oligosaccharides.Moreover,ulvan oligosaccharides at 2 mg/m L could almost completely blocked α-syn aggregation.Through atomic force microscopy studies,it was found that both ulvan polysaccharides and oligosaccharides could significantly change the aggregation morphology of α-syn to form short or amorphous aggregates and inhibit long fibers formation.The results of dot blot assay showed that ulvan polysaccharides and oligosaccharides reduced the production of oligomers and mature fibers in a concentrationdependent manner.In addition,cell experimental data indicated that ulvan polysaccharides and oligosaccharides could significantly reduce the cytotoxicity induced by α-syn aggregates.And ulvan polysaccharides or oligosaccharides at 2 mg/m L restored cell viability to71.47%and 90.86%,respectively.Furthermore,ulvan polysaccharides or oligosaccharides could also degrade α-syn mature fibers to form less toxic aggregates,and the higher the compound concentration,the stronger the degradation effect.Finally,the inhibition effects of ulvan polysaccharides and oligosaccharides on α-syn fibrillogenesis in vivo were investigated using transgenic nematode NL5901 expressing human α-syn.The results showed that ulvan polysaccharides or oligosaccharides could significantly inhibit α-syn accumulation,restore the lipid reduction caused by α-syn accumulation.And the lifespan of nematodes was increased by 1.6 and 1.2 d,respectively.Combined with the above results,it is shown that ulvan polysaccharides and oligosaccharides are potent inhibitors that can inhibit α-syn aggregation and depolymerize-syn mature fibers.At the same time,they can reduce α-syn-induced cytotoxicity and prolong the lifespan of nematodes.So ulvan polysaccharides and oligosaccharides are expected to be potential agents for treating PD caused by α-syn aggregation.