Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the m...Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.展开更多
Parkinson's disease is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta,which leads to the featured motor impairment of p...Parkinson's disease is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta,which leads to the featured motor impairment of parkinsonism,including akinesia,bradykinesia,rigidity,and tremor(McGregor and Nelson,2019).展开更多
A range of neurodegenerative disorders,collectively termed parkinsonian disorders,present with a complex array of both motor and non-motor symptoms.Included in this group are Parkinson’s disease(PD),dementia with Lew...A range of neurodegenerative disorders,collectively termed parkinsonian disorders,present with a complex array of both motor and non-motor symptoms.Included in this group are Parkinson’s disease(PD),dementia with Lewy bodies(DLB),multiple system atrophy(MSA),corticobasal syndrome(CBS),and progressive supranuclear palsy(PSP).These disorders are differentiated neuropathologically by their dominant protein pathologies involvingα-synuclein(α-syn)and/or tau,the types of brain cells affected,such as neurons,oligodendroglia,and astrocytes,and the specific brain regions involved(Tolosa et al.,2021).展开更多
Objective Keshan disease(KD)is a myocardial mitochondrial disease closely related to insufficient selenium(Se)and protein intake.PTEN induced putative kinase 1(PINK1)/Parkin mediated mitochondrial autophagy regulates ...Objective Keshan disease(KD)is a myocardial mitochondrial disease closely related to insufficient selenium(Se)and protein intake.PTEN induced putative kinase 1(PINK1)/Parkin mediated mitochondrial autophagy regulates various physiological and pathological processes in the body.This study aimed to elucidate the relationship between PINK1/Parkin-regulated mitochondrial autophagy and KD-related myocardial injury.Methods A low Se and low protein animal model was established.One hundred Wistar rats were randomly divided into 5 groups(control group,low Se group,low protein group,low Se+low protein group,and corn from KD area group).The JC-1 method was used to detect the mitochondrial membrane potential(MMP).ELISA was used to detect serum creatine kinase MB(CK-MB),cardiac troponin I(cTnI),and mitochondrial-glutamicoxalacetic transaminase(M-GOT)levels.RT-PCR and Western blot analysis were used to detect the expression of PINK1,Parkin,sequestome 1(P62),and microtubule-associated proteins1A/1B light chain 3B(MAP1LC3B).Results The MMP was significantly decreased and the activity of CK-MB,cTnI,and M-GOT significantly increased in each experimental group(low Se group,low protein group,low Se+low protein group and corn from KD area group)compared with the control group(P<0.05 for all).The mRNA and protein expression levels of PINK1,Parkin and MAP1LC3B were profoundly increased,and those of P62 markedly decreased in the experimental groups compared with the control group(P<0.05 for all).Conclusion Low Se and low protein levels exacerbate myocardial damage in KD by affecting the PINK1/Parkin-mediated mitochondrial autophagy pathway.展开更多
基金supported by the Key Science and Technology Research of Henan Province,No.222102310351(to JW)Luoyang 2022 Medical and Health Guiding Science and Technology Plan Project,No.2022057Y(to JY)Henan Medical Science and Technology Research Program Province-Ministry Co-sponsorship,No.SBGJ202002099(to JY)。
文摘Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson s disease,but the regulato ry mechanism remains elusive.Prohibitin-2(PHB2)is a newly discove red autophagy receptor in the mitochondrial inner membrane,and its role in Parkinson’s disease remains unclear.Protein kinase R(PKR)-like endoplasmic reticulum kinase(PERK)is a factor that regulates cell fate during endoplasmic reticulum stress.Parkin is regulated by PERK and is a target of the unfolded protein response.It is unclear whether PERK regulates PHB2-mediated mitophagy thro ugh Parkin.In this study,we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of Parkinson’s disease.We used adeno-associated virus to knockdown PHB2 expression.Our res ults showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson’s disease.Ove rexpression of PHB2 inhibited these abnormalities.We also established a 1-methyl-4-phenylpyridine(MPP+)-induced SH-SY5Y cell model of Parkinson’s disease.We found that ove rexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3,and promoted mitophagy.In addition,MPP+regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK.These findings suggest that PHB2 participates in the development of Parkinson’s disease by intera cting with endoplasmic reticulum stress and Parkin.
文摘近年来,我国脑卒中总体发病率呈上升趋势,其以发病突然、起病急骤的神经功能缺损为主要特征[1]。脑卒中主要包括缺血性脑卒中(ischemic stroke,IS)和出血性脑卒中两大类,而最常见的类型是IS。IS导致神经细胞血液供应不足,所需的葡萄糖和氧气减少,神经细胞稳态被扰乱,从而引发包括兴奋性毒性、氧化应激、炎症、细胞凋亡在内的病理生理过程[2]。研究表明,线粒体自噬可以及时清除受损的线粒体,有效控制线粒体质量和功能,维持神经细胞稳态和防止神经细胞凋亡,在IS病理生理过程中起着不可忽视的作用[3]。现就PTEN诱导推定激酶1(PTEN-induced putative kinase protein 1,PINK1)/人帕金森蛋白2(human Parkinson disease protein 2,Parkin)介导线粒体自噬对IS作用机制的研究进展予以综述。
基金supported in part by the research grant from the National Institute of Neurological Disorders and Stroke,No.R01NS 12137 (to HYC)funded in whole or in part by Aligning Science Across Parkinson's (No.ASA P-0205 720) through the Michael J.Fox Foundation for Parkinson's Research (MJFF)。
文摘Parkinson's disease is a chronic and progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta,which leads to the featured motor impairment of parkinsonism,including akinesia,bradykinesia,rigidity,and tremor(McGregor and Nelson,2019).
文摘A range of neurodegenerative disorders,collectively termed parkinsonian disorders,present with a complex array of both motor and non-motor symptoms.Included in this group are Parkinson’s disease(PD),dementia with Lewy bodies(DLB),multiple system atrophy(MSA),corticobasal syndrome(CBS),and progressive supranuclear palsy(PSP).These disorders are differentiated neuropathologically by their dominant protein pathologies involvingα-synuclein(α-syn)and/or tau,the types of brain cells affected,such as neurons,oligodendroglia,and astrocytes,and the specific brain regions involved(Tolosa et al.,2021).
基金supported by the Natural Science Foundation of Heilongjiang Province(No.LH2021H009).
文摘Objective Keshan disease(KD)is a myocardial mitochondrial disease closely related to insufficient selenium(Se)and protein intake.PTEN induced putative kinase 1(PINK1)/Parkin mediated mitochondrial autophagy regulates various physiological and pathological processes in the body.This study aimed to elucidate the relationship between PINK1/Parkin-regulated mitochondrial autophagy and KD-related myocardial injury.Methods A low Se and low protein animal model was established.One hundred Wistar rats were randomly divided into 5 groups(control group,low Se group,low protein group,low Se+low protein group,and corn from KD area group).The JC-1 method was used to detect the mitochondrial membrane potential(MMP).ELISA was used to detect serum creatine kinase MB(CK-MB),cardiac troponin I(cTnI),and mitochondrial-glutamicoxalacetic transaminase(M-GOT)levels.RT-PCR and Western blot analysis were used to detect the expression of PINK1,Parkin,sequestome 1(P62),and microtubule-associated proteins1A/1B light chain 3B(MAP1LC3B).Results The MMP was significantly decreased and the activity of CK-MB,cTnI,and M-GOT significantly increased in each experimental group(low Se group,low protein group,low Se+low protein group and corn from KD area group)compared with the control group(P<0.05 for all).The mRNA and protein expression levels of PINK1,Parkin and MAP1LC3B were profoundly increased,and those of P62 markedly decreased in the experimental groups compared with the control group(P<0.05 for all).Conclusion Low Se and low protein levels exacerbate myocardial damage in KD by affecting the PINK1/Parkin-mediated mitochondrial autophagy pathway.
