Background Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic(DA)neurons,which may serve as an intrinsic neuroprotective mechanism in Parkinson’s disease(PD).LRRK2 G2019S is...Background Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic(DA)neurons,which may serve as an intrinsic neuroprotective mechanism in Parkinson’s disease(PD).LRRK2 G2019S is the most common pathogenic mutation associated with PD.In this study,we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation.Methods DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation.A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S.Results Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons.Compared with the co-culture system from the healthy participant,the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage.Specifically,STX17 was colocalized with the mitochondrial outer membrane marker TOM20,and its knockdown caused damage to mitochondrial transfer.Drp1 interacted with STX17.LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure.Moreover,the degree of colocalization of STX17 with TOM20 decreased.The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20,as well as the mitochondrial transfer efficiency and neuronal survival.Conclusions The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation.The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway.Notably,inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments.This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.展开更多
基金supported by the National Natural Science Foundation of China(82101333 to X.-Y.C.)The Gusu Health Talents Project(GSWS2022035 to X.-Y.C.)+3 种基金Jiangsu Provincial Medical Key Discipline(ZDXK202217 to C.-F.L.)Suzhou Key Laboratory of Sleep Disorders Diagnosis and Treatment Technology(SZS2023015 to C.-F.L.)Xiongan New Area Science and Technology Innovation Project(2023XAGG0073 to C.-F.L.)Natural Science Foundation of Jiangsu Province(BK20240356 to M.C.).
文摘Background Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic(DA)neurons,which may serve as an intrinsic neuroprotective mechanism in Parkinson’s disease(PD).LRRK2 G2019S is the most common pathogenic mutation associated with PD.In this study,we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation.Methods DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation.A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S.Results Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons.Compared with the co-culture system from the healthy participant,the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage.Specifically,STX17 was colocalized with the mitochondrial outer membrane marker TOM20,and its knockdown caused damage to mitochondrial transfer.Drp1 interacted with STX17.LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure.Moreover,the degree of colocalization of STX17 with TOM20 decreased.The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20,as well as the mitochondrial transfer efficiency and neuronal survival.Conclusions The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation.The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway.Notably,inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments.This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.
