Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1^G93A Transgenic Mice Via Activation of Mitophagy

Zhang, Huan1; Gao, Chuanyue1,2; Yang, Deguang3; Nie, Lulin1,4; He, Kaiwu1; Chen, Chongyang1; Li, Shangming1; Huang, Guanqin1; Zhou, Li1; Huang, Xinfeng1; Wu, Desheng1; Liu, Jianjun1; Huang, Zhenlie5; Wang, Jie6; Li, Weihua7; Zhang, Zhaohui8; Yang, Xifei1; Zou, Liangyu6

2024-09-01

10.1007/s12035-024-04473-1

MOLECULAR NEUROBIOLOGY   影响因子和分区

0893-7648

1559-1182

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease pathologically characterized by selective degeneration of motor neurons resulting in a catastrophic loss of motor function. The present study aimed to investigate the effect of copper (Cu) exposure on progression of ALS and explore the therapeutic effect and mechanism of Urolithin A (UA) on ALS. 0.13 PPM copper chloride drinking water was administrated in SOD1(G93A) transgenic mice at 6 weeks, UA at a dosage of 50 mg/kg/day was given for 6 weeks after a 7-week Cu exposure. Motor ability was assessed before terminal anesthesia. Muscle atrophy and fibrosis, motor neurons, astrocytes and microglia in the spinal cord were evaluated by H&E, Masson, Sirius Red, Nissl and Immunohistochemistry Staining. Proteomics analysis, Western blotting and ELISA were conducted to detect protein expression. Mitochondrial adenosine triphosphate (ATP) and malondialdehyde (MDA) levels were measured using an assay kit. Cu-exposure worsened motor function, promoted muscle fibrosis, loss of motor neurons, and astrocyte and microglial activation. It also induced abnormal changes in mitochondria-related biological processes, leading to a significant reduction in ATP levels and an increase in MDA levels. Upregulation of P62 and downregulation of Parkin, PINK1, and LAMP1 were revealed in SOD1(G93A) mice with Cu exposure. Administration of UA activated mitophagy, modulated mitochondria dysfunction, reduced neuroinflammation, and improved gastrocnemius muscle atrophy and motor dysfunction in SOD1(G93A) mice with Cu exposure. Mitophagy plays critical role in ALS exacerbated by Cu exposure. UA administration may be a promising treatment strategy for ALS.

Amyotrophic lateral sclerosis Copper Mitophagy Motor dysfunction Urolithin A

SCI

英语

通讯

NSFC[82171583] ; Key Basic Research Program of Shenzhen Science and Technology Innovation Commission["JCYJ20200109150717745","JCYJ20200109144418639"] ; Shenzhen Key Medical Discipline Construction Fund[SZXK069] ; Sanming Project of Medicine in Shenzhen[SZSM201611090] ; Study on Photothermal tumor Vaccine, Shenzhen Science and Technology Innovation Commission[JCYJ20200109120205924]

Neurosciences & Neurology

Neurosciences

WOS:001327532000003

SPRINGER

Web of Science

1.Shenzhen Ctr Dis Control & Prevent, Shenzhen Key Lab Modern Toxicol, Shenzhen Med Key Discipline Hlth Toxicol 2020 2024, Shenzhen 518055, Peoples R China
2.Xian Int Med Ctr Hosp, Xian 710100, Peoples R China
3.Jinan Univ, Affiliated Hosp 5, Heyuan Shenhe Peoples Hosp, Dept Cardiol, Heyuan 517000, Peoples R China
4.Jinan Univ, Coll Pharm, Guangzhou 510632, Peoples R China
5.Southern Med Univ, Sch Publ Hlth, NMPA Key Lab Safety Evaluat Cosmet, Guangdong Prov Key Lab Trop Dis Res,Dept Toxicol, Guangzhou 510515, Peoples R China
6.Southern Univ Sci & Technol, Jinan Univ, Affiliated Hosp 1, Shenzhen Peoples Hosp,Clin Med Coll 2,Dept Neurol, Shenzhen, Peoples R China
7.Shenzhen Univ, Shenzhen Peoples Hosp 2, Dept Med imaging, Affiliated Hosp 1,Hlth Sci Ctr, Shenzhen 518035, Peoples R China
8.Univ South China, Sch Publ Hlth, Hengyang 421001, Hunan, Peoples R China

Zhang, Huan,Gao, Chuanyue,Yang, Deguang,et al. Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1^G93A Transgenic Mice Via Activation of Mitophagy[J]. MOLECULAR NEUROBIOLOGY,2024.

Zhang, Huan.,Gao, Chuanyue.,Yang, Deguang.,Nie, Lulin.,He, Kaiwu.,...&Zou, Liangyu.(2024).Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1^G93A Transgenic Mice Via Activation of Mitophagy.MOLECULAR NEUROBIOLOGY.

Zhang, Huan,et al."Urolithin a Improves Motor Dysfunction Induced by Copper Exposure in SOD1^G93A Transgenic Mice Via Activation of Mitophagy".MOLECULAR NEUROBIOLOGY (2024).