2010
DOI: 10.1111/j.1471-4159.2010.06894.x
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The G2019S pathogenic mutation disrupts sensitivity of leucine‐rich repeat kinase 2 to manganese kinase inhibition

Abstract: J. Neurochem. (2010) 115, 36–46. Abstract Mutations in leucine‐rich repeat kinase‐2 (LRRK2) are the most common cause of late‐onset Parkinson disease. Previously, we showed that the G2019S pathogenic mutation can cause a dramatic increase (approximately 10‐fold) in kinase activity, far above other published studies. A notable experimental difference was the use of Mn‐ATP as a substrate. Therefore, the effects of metal cation‐ATP cofactors on LRRK2 kinase activity were investigated. It is shown, using several d… Show more

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Cited by 19 publications
(30 citation statements)
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References 62 publications
(155 reference statements)
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“…The efficiency of ATP-mediated kinase activity for WT and G2019S LRRK2 both increased by ~14 and ~8 fold, respectively, compared to Mg 2+ reactions (Figure 2E, F). These results are consistent with previous observations for the effects of Mn 2+ on LRRK2 kinase activity [18, 30]. Therefore, Mn 2+ -bound G2019S LRRK2 showed a large increase (>10-fold) in kinase activity for both autophosphorylation and peptide phosphorylation when either GTP or ATP are used as phospho-donors.…”
Section: Resultssupporting
confidence: 92%
See 1 more Smart Citation
“…The efficiency of ATP-mediated kinase activity for WT and G2019S LRRK2 both increased by ~14 and ~8 fold, respectively, compared to Mg 2+ reactions (Figure 2E, F). These results are consistent with previous observations for the effects of Mn 2+ on LRRK2 kinase activity [18, 30]. Therefore, Mn 2+ -bound G2019S LRRK2 showed a large increase (>10-fold) in kinase activity for both autophosphorylation and peptide phosphorylation when either GTP or ATP are used as phospho-donors.…”
Section: Resultssupporting
confidence: 92%
“…We therefore substituted Mn 2+ for Mg 2+ and with this increased efficiency we could develop robust GTP-mediated kinase activity. Further, in our experiments using a protein fragment of LRRK2 that lacks the N-terminal domain, we were able to replicate a previously reported finding in full-length LRRK2 protein that G2019S LRRK2 in the Mn 2+ bound state shows a much larger increase in kinase activity relative to WT LRRK2 than Mg 2+ bound LRRK2 [30]. …”
Section: Discussionsupporting
confidence: 81%
“…A vital strategy for enhancing recovery from contusive SCI is remyelination. In vitro , NGF and BDNF exhibit a promyelinating influence on DRG explants via activation of neuronally expressed TrkA and oligodendroglial TrkB-FL receptors (Chan et al, 2004; Xiao et al, 2010) respectively. In contrast, in vitro , exogenous NT-3 has been shown to have an inhibitory effect on Schwann cell dependent myelination (Chan et al, 2001; Cosgaya et al, 2002).…”
Section: Nt Treatment Increase Regeneration After Spinal Cord Injury mentioning
confidence: 99%
“…These observations are particularly relevant to Mn toxicity as Mn can also perturb dopaminergic function (Peneder et al , 2011; Sriram et al , 2010) and inhibit amphetamine-induced DA release (Guilarte et al , 2008) as well as promote mitochondria degeneration. Interestingly, Mn can increase the activity of the most prevalent mutant form of LRRK2, G2019S, but inhibit wild-type kinase activity which is normally stimulated by Mg (Covy and Giasson, 2010; Lovitt et al , 2010). Thus, LRRK2 displays a number of critical functions many of which can affect or be affected by Mn.…”
Section: 0 Discussionmentioning
confidence: 99%