PubMed:26546614 JSON TXT

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PubTator4TogoVar

{"project":"PubTator4TogoVar","denotations":[{"id":"26546614_0","span":{"begin":678,"end":684},"obj":"ProteinMutation"},{"id":"26546614_1","span":{"begin":834,"end":840},"obj":"ProteinMutation"},{"id":"26546614_2","span":{"begin":987,"end":993},"obj":"ProteinMutation"},{"id":"26546614_3","span":{"begin":1016,"end":1022},"obj":"ProteinMutation"},{"id":"26546614_4","span":{"begin":1202,"end":1208},"obj":"ProteinMutation"},{"id":"26546614_5","span":{"begin":1263,"end":1269},"obj":"ProteinMutation"},{"id":"26546614_6","span":{"begin":1433,"end":1439},"obj":"ProteinMutation"}],"attributes":[{"id":"26546614_0_ProteinMutation","pred":"proteinmutation","subj":"26546614_0","obj":"rs34637584"},{"id":"26546614_1_ProteinMutation","pred":"proteinmutation","subj":"26546614_1","obj":"rs33939927"},{"id":"26546614_2_ProteinMutation","pred":"proteinmutation","subj":"26546614_2","obj":"rs34637584"},{"id":"26546614_3_ProteinMutation","pred":"proteinmutation","subj":"26546614_3","obj":"rs34637584"},{"id":"26546614_4_ProteinMutation","pred":"proteinmutation","subj":"26546614_4","obj":"rs34637584"},{"id":"26546614_5_ProteinMutation","pred":"proteinmutation","subj":"26546614_5","obj":"rs34637584"},{"id":"26546614_6_ProteinMutation","pred":"proteinmutation","subj":"26546614_6","obj":"rs34637584"}],"text":"14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.\nMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3θ overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels. Similarly, 14-3-3θ overexpression reversed neurite shortening in neuronal cultures from BAC transgenic R1441G-LRRK2 mice. Conversely, inhibition of 14-3-3s by the pan-14-3-3 inhibitor difopein or dominant-negative 14-3-3θ further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3θ's effects on LRRK2 kinase activity. 14-3-3θ overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3θ to reduce LRRK2 kinase activity required direct binding of 14-3-3θ with LRRK2. The potentiation of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors. Taken together, we conclude that 14-3-3θ can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity."}

c_corpus

UseCases_ArguminSci_Discourse

{"project":"UseCases_ArguminSci_Discourse","denotations":[{"id":"T1","span":{"begin":0,"end":77},"obj":"DRI_Background"},{"id":"T2","span":{"begin":78,"end":244},"obj":"DRI_Approach"},{"id":"T3","span":{"begin":245,"end":300},"obj":"DRI_Background"},{"id":"T4","span":{"begin":301,"end":459},"obj":"DRI_Background"},{"id":"T5","span":{"begin":460,"end":580},"obj":"DRI_Approach"},{"id":"T6","span":{"begin":581,"end":730},"obj":"DRI_Background"},{"id":"T7","span":{"begin":731,"end":852},"obj":"DRI_Background"},{"id":"T8","span":{"begin":853,"end":926},"obj":"DRI_Background"},{"id":"T9","span":{"begin":927,"end":952},"obj":"Token_Label.OUTSIDE"},{"id":"T10","span":{"begin":953,"end":1009},"obj":"DRI_Background"},{"id":"T11","span":{"begin":1010,"end":1147},"obj":"DRI_Background"},{"id":"T12","span":{"begin":1148,"end":1276},"obj":"DRI_Background"},{"id":"T13","span":{"begin":1277,"end":1378},"obj":"DRI_Challenge"},{"id":"T14","span":{"begin":1379,"end":1494},"obj":"DRI_Background"},{"id":"T15","span":{"begin":1495,"end":1634},"obj":"DRI_Approach"}],"text":"14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.\nMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3θ overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels. Similarly, 14-3-3θ overexpression reversed neurite shortening in neuronal cultures from BAC transgenic R1441G-LRRK2 mice. Conversely, inhibition of 14-3-3s by the pan-14-3-3 inhibitor difopein or dominant-negative 14-3-3θ further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3θ's effects on LRRK2 kinase activity. 14-3-3θ overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3θ to reduce LRRK2 kinase activity required direct binding of 14-3-3θ with LRRK2. The potentiation of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors. Taken together, we conclude that 14-3-3θ can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity."}

PubMed_ArguminSci

{"project":"PubMed_ArguminSci","denotations":[{"id":"T1","span":{"begin":78,"end":244},"obj":"DRI_Approach"},{"id":"T2","span":{"begin":245,"end":300},"obj":"DRI_Background"},{"id":"T3","span":{"begin":301,"end":459},"obj":"DRI_Background"},{"id":"T4","span":{"begin":460,"end":580},"obj":"DRI_Approach"},{"id":"T5","span":{"begin":581,"end":730},"obj":"DRI_Background"},{"id":"T6","span":{"begin":731,"end":852},"obj":"DRI_Background"},{"id":"T7","span":{"begin":853,"end":926},"obj":"DRI_Background"},{"id":"T8","span":{"begin":953,"end":1009},"obj":"DRI_Background"},{"id":"T9","span":{"begin":1010,"end":1147},"obj":"DRI_Background"},{"id":"T10","span":{"begin":1148,"end":1276},"obj":"DRI_Background"},{"id":"T11","span":{"begin":1277,"end":1378},"obj":"DRI_Challenge"},{"id":"T12","span":{"begin":1379,"end":1494},"obj":"DRI_Background"},{"id":"T13","span":{"begin":1495,"end":1634},"obj":"DRI_Approach"}],"text":"14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening.\nMutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson's disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3θ overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wild-type levels. Similarly, 14-3-3θ overexpression reversed neurite shortening in neuronal cultures from BAC transgenic R1441G-LRRK2 mice. Conversely, inhibition of 14-3-3s by the pan-14-3-3 inhibitor difopein or dominant-negative 14-3-3θ further reduced neurite length in G2019S-LRRK2 cultures. Since G2019S-LRRK2 toxicity is likely mediated through increased kinase activity, we examined 14-3-3θ's effects on LRRK2 kinase activity. 14-3-3θ overexpression reduced the kinase activity of G2019S-LRRK2, while difopein promoted the kinase activity of G2019S-LRRK2. The ability of 14-3-3θ to reduce LRRK2 kinase activity required direct binding of 14-3-3θ with LRRK2. The potentiation of neurite shortening by difopein in G2019S-LRRK2 neurons was reversed by LRRK2 kinase inhibitors. Taken together, we conclude that 14-3-3θ can regulate LRRK2 and reduce the toxicity of mutant LRRK2 through a reduction of kinase activity."}

DisGeNET5_gene_disease