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
Interstitial lung disease （ILD） is a comprehensive term referring to a group of lung diseases affecting the interstitium of the lung. Idiopathic pulmonary fibrosis （IPF） is the most common idiopathic ILD, and nons...Interstitial lung disease （ILD） is a comprehensive term referring to a group of lung diseases affecting the interstitium of the lung. Idiopathic pulmonary fibrosis （IPF） is the most common idiopathic ILD, and nonspecific interstitial pneumonia （NSIP） is the second most common. As the name suggests, NSIP is diagnosed atter many other diseases are excluded. The main pathological finding in NSIP is homogeneous interstitial inflammation with or without fibrosis. NSIP can be categorized by cellular type or fibrotic type, according to the grade of inflammation and fibrosis. The cellular type has mostly inflammatory lesions with good responses to steroid, but the fibrotic type has a large proportion of fibrosis mixed with inflammatory lesions and a relatively poor response to steroid treatment So far, the exact mechanism underlying idiopathic lED has not been clarified. Determining key regulators of these ILDs will be helpful in the diagnosis and development of novel drugs for ILD.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.
文摘Interstitial lung disease （ILD） is a comprehensive term referring to a group of lung diseases affecting the interstitium of the lung. Idiopathic pulmonary fibrosis （IPF） is the most common idiopathic ILD, and nonspecific interstitial pneumonia （NSIP） is the second most common. As the name suggests, NSIP is diagnosed atter many other diseases are excluded. The main pathological finding in NSIP is homogeneous interstitial inflammation with or without fibrosis. NSIP can be categorized by cellular type or fibrotic type, according to the grade of inflammation and fibrosis. The cellular type has mostly inflammatory lesions with good responses to steroid, but the fibrotic type has a large proportion of fibrosis mixed with inflammatory lesions and a relatively poor response to steroid treatment So far, the exact mechanism underlying idiopathic lED has not been clarified. Determining key regulators of these ILDs will be helpful in the diagnosis and development of novel drugs for ILD.
