Research On The Effect And Mechanism Of Itaconic Acid Inhibits α-Syn Aggregation In C.elegans By Autophagy

Parkinson’s disease（PD）is a typical neurodegenerative disease,with a lower incidence rate than Alzheimer’s disease.However,due to the rapid growth of the global aging population,the growth rate of Parkinson’s disease is far faster than that of other nervous system disease in terms of morbidity and mortality.The signature pathological feature of the disease is the accumulation of misfoldedα-Synuclein（α-Syn）,alongside the progressive loss of dopaminergic neurons located in the midbrain.This leads to reduced release of dopamine neurotransmitters from striatal nerve endings,resulting in clinical motor symptoms such as static tremors,muscle stiffness,slow movement,and abnormal gait.PD patients also experience non-motor symptoms such as loss of sense of smell,decreased intestinal peristalsis,cardiovascular dysfunction,emotional and cognitive disorders,and sleep disorders.Under the interference of genetic factors and external environment,PD patients are now being diagnosed at a younger age.Currently,China has become the country with the highest number of PD patients,with half of the global PD patients concentrated in China.This potential public health crisis will bring a heavy burden to families and society.Itaconic acid,also known as methylene succinic acid,is an unsaturated dicarboxylic acid that acts as an intermediate metabolite of the tricarboxylic acid cycle in mammals.It plays a vital role in mediating the interaction between infection,immunity,and metabolism.Early research conducted in our laboratory has shown that Itaconic acid by activation of mitochondrial protein folding reaction(Mitochondrial unfolded protein response,UPR^mt)to extend the C.elegans（Caenorhabditis elegans,C.elegans）health life.This suggests the role of Itaconic acid in regulating protein homeostasis,and autophagy is the primary means for maintaining protein homeostasis.We speculate that Itaconic acid may be involved in autophagy and have a potential therapeutic role in the treatment of neurodegenerative diseases.This study aimed to explore the effects of Itaconic acid on the C.elegans PD model ofα-Syn aggregation.It involved the use of q RT-PCR and RNA interference（RNAi）technology to verify whether Itaconic acid induces autophagy and affects PD.The research findings showed that Itaconic acid improved the lifespan and motor function of the PD model C.elegans,significantly reducingα-Syn aggregates in the PD model C.elegans NL5901 and displaying a protective effect on DA neurons.At the same time,using a fluorescence microscope,the effect of Itaconic acid on the number of autophagosomes and autophagosomes was detected,and the results indicated that Itaconic acid can promote the production of autophagic flow.By detecting the transcription levels of autophagy-related genes,the researchers found that Itaconic acid effectively increased the expression levels of genes such as pink-1,bec-1,vps-34,Igg-1,and Igg-2.Subsequently,RNAi interference technology was used to reduce the expression of pink-1,bec-1,and sqst-1,and Itaconic acid cleared the aggregationα-Syn ability significantly decreased.The above results indicate that Itaconic acid can induce autophagy in PD model C.elegans,Which can reduce the aggregation ofα-Syn and improve the survival of PD model C.elegans NL5901.