Background:Leucine-rich repeat kinase 2(LRRK2)mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease(PD).Especially,LRRK2 G2019S missense mutation has been identified as the mo...Background:Leucine-rich repeat kinase 2(LRRK2)mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease(PD).Especially,LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD.Advanced glycation end products(AGEs)are produced in high amounts in diabetes and diverse aging-related disorders,such as cardiovascular disease,renal disease,and neurological disease.AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death.RAGE,receptor of AGEs,is activated by interaction with AGEs and mediates AGE-induced cytotoxicity.Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown.Methods:Using cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type(WT)and G2019S transgenic mice,we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining.We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots.Results:We show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls.Furthermore,we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells.Conclusions:These data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD.展开更多
Parkinson’s disease(PD)is a multifaceted disease in which environmental variables combined with genetic predisposition cause dopaminergic(DAergic)neuron loss in the substantia nigra pars compacta.The mutation of leuc...Parkinson’s disease(PD)is a multifaceted disease in which environmental variables combined with genetic predisposition cause dopaminergic(DAergic)neuron loss in the substantia nigra pars compacta.The mutation of leucine-rich repeat kinase 2(Lrrk2)is the most common autosomal dominant mutation in PD,and it has also been reported in sporadic cases.A growing body of research suggests that circadian rhythm disruption,particularly sleep-wake abnormality,is common during the early phase of PD.Our present study aimed to evaluate the impact of sleep deprivation(SD)on motor ability,sleep performance,and PD pathologies in Lrrk2^(G2019S) transgenic mice.After two months of SD,Lrrk2^(G2019S) mice at 12 months of age showed an exacerbated PD-like phenotype with motor deficits,a reduced striatal DA level,degenerated DAergic neurons,and altered sleep structure and biological rhythm accompanied by the decreased protein expression level of circadian locomotor output cycles kaput Lrrk2 gene in the brain.All these changes persisted and were even more evident in 18-month-old mice after 6 months of follow-up.Moreover,a significant increase inα-synuclein aggregation was found in SD-treated transgenic mice at 18 months of age.Taken together,our findings indicate that sleep abnormalities,as a risk factor,may contribute to the pathogenesis and progression of PD.Early detection of sleep disorders and improvement of sleep quality may help to delay disease progression and provide long-term clinical benefits.展开更多
基金This work was supported by the intramural research programs of National Institute on Aging,National Institutes of Health(HC:AG000944).
文摘Background:Leucine-rich repeat kinase 2(LRRK2)mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease(PD).Especially,LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD.Advanced glycation end products(AGEs)are produced in high amounts in diabetes and diverse aging-related disorders,such as cardiovascular disease,renal disease,and neurological disease.AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death.RAGE,receptor of AGEs,is activated by interaction with AGEs and mediates AGE-induced cytotoxicity.Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown.Methods:Using cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type(WT)and G2019S transgenic mice,we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining.We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots.Results:We show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls.Furthermore,we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells.Conclusions:These data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD.
基金We thank Liaoning Provincial Center for Clinical Research on Neurological Diseases,the First Affiliated Hospital,and Dalian Medical University for the research infrastructure and support.This work was supported by the National Natural Science Foundation of China(81771521).
文摘Parkinson’s disease(PD)is a multifaceted disease in which environmental variables combined with genetic predisposition cause dopaminergic(DAergic)neuron loss in the substantia nigra pars compacta.The mutation of leucine-rich repeat kinase 2(Lrrk2)is the most common autosomal dominant mutation in PD,and it has also been reported in sporadic cases.A growing body of research suggests that circadian rhythm disruption,particularly sleep-wake abnormality,is common during the early phase of PD.Our present study aimed to evaluate the impact of sleep deprivation(SD)on motor ability,sleep performance,and PD pathologies in Lrrk2^(G2019S) transgenic mice.After two months of SD,Lrrk2^(G2019S) mice at 12 months of age showed an exacerbated PD-like phenotype with motor deficits,a reduced striatal DA level,degenerated DAergic neurons,and altered sleep structure and biological rhythm accompanied by the decreased protein expression level of circadian locomotor output cycles kaput Lrrk2 gene in the brain.All these changes persisted and were even more evident in 18-month-old mice after 6 months of follow-up.Moreover,a significant increase inα-synuclein aggregation was found in SD-treated transgenic mice at 18 months of age.Taken together,our findings indicate that sleep abnormalities,as a risk factor,may contribute to the pathogenesis and progression of PD.Early detection of sleep disorders and improvement of sleep quality may help to delay disease progression and provide long-term clinical benefits.
