ArticleJournal of neurochemistry2010
The G2019S pathogenic mutation disrupts sensitivity of leucine-rich repeat kinase 2 to manganese kinase inhibition.
Article in Journal of neurochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 22 citations in OpenAlex.
- Regulation of LRRK2 activity by metabolic stress and heavy metal exposure.Brain research · 2025Article
- Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues.Cells · 2020Article
- The dual enzyme LRRK2 hydrolyzes GTP in both its GTPase and kinase domains in vitro.Biochimica et biophysica acta. Proteins and proteomics · 2017Article
- The Central Role of Biometals Maintains Oxidative Balance in the Context of Metabolic and Neurodegenerative Disorders.Oxidative medicine and cellular longevity · 2017Review
- Physiologically relevant factors influence tau phosphorylation by leucine-rich repeat kinase 2.Journal of neuroscience research · 2015Article
- LRRK2 phosphorylates novel tau epitopes and promotes tauopathy.Acta neuropathologica · 2013Article
- Down-regulation of LRRK2 in control and DAT transfected HEK cells increases manganese-induced oxidative stress and cell toxicity.Neurotoxicology · 2013Article
- Manganese in health and disease.Metal ions in life sciences · 2013Review
- Manganese homeostasis and transport.Metal ions in life sciences · 2013Article
- X-ray fluorescence analysis of iron and manganese distribution in primary dopaminergic neurons.Journal of neurochemistry · 2013Article
- ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese.Neurotoxicology · 2012Article
- Biochemical characterization of highly purified leucine-rich repeat kinases 1 and 2 demonstrates formation of homodimers.PloS one · 2012Article
- α-Synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of Parkinson disease.Neurotoxicology · 2011Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
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 divalent metal cations, that only Mg(2+) or Mn(2+) can support LRRK2 kinase activity. However, for wild-type, I2020T, and R1441C LRRK2, Mn(2+) was significantly less effective at supporting kinase activity. In sharp contrast, both Mn(2+) and Mg(2+) were effective at supporting the activity of G2019S LRRK2. These divergent effects associated with divalent cation usage and the G2019S mutation were predominantly because of differences in catalytic rates. However, LRRK2 was shown to have much lower (approximately 40-fold) ATP K(m) for Mn-ATP compared with Mg-ATP. Consequently, sub-stoichiometric concentrations of Mn(2+) can act to inhibit the kinase activity of wild-type, but not G2019S LRRK2 in the presence of Mg(2+) . From these findings, a new model is proposed for a possible function of LRRK2 and the consequence of the G2019S LRRK2 pathogenic mutation.
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