Abstract
Parkinson’s disease (PD) is a common neurodegenerative disease with unclear pathogenesis. Currently, there are no disease-modifying neuron-protecting drugs to slow down the neuronal degeneration. Mutations in the leucine-rich repeat kinase 2 (LRRK2) cause genetic forms of PD and contribute to sporadic PD as well. Disruption of LRRK2 kinase functions has become one of the potential mechanisms underlying disease-linked mutation-induced neuronal degeneration. To further characterize the pharmacological effects of a reported LRRK2 kinase inhibitor, LDN-73794, in vitro cell models and a LRRK2 Drosophila PD model were used. LDN-73794 reduced LRRK2 kinase activity in vitro and in vivo. Moreover, LDN-73794 increased survival, improved locomotor activity, and suppressed DA neuron loss in LRRK2 transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing neuroprotective therapeutics.
Highlights
Parkinson’s disease (PD) is a common age-related progressive neurodegenerative disease with two pathologicalHow to cite this paper: Yang, D.J., Das, S., Song, L.J., Li, T.X., Yan, J.Q. and Smith, W.W. (2015) LDN-73794 Attenuated leucine-rich repeat kinase 2 (LRRK2)-Induced Degeneration in a Drosophila Parkinson’s Disease Model
This is consistent with the previously findings that LDN-73794 reduced LRRK2 kinase activity using a PLK-peptide as a substrate [30]
LDN-73794 reduced G2019S-LRRK2 phosphorylation in brains of transgenic flies. These results suggest that inhibition of LRRK2 kinase activity can be a potential therapeutic strategy for PD intervention and LDN-73794 could be a potential lead compound for developing novel therapeutics
Summary
Parkinson’s disease (PD) is a common age-related progressive neurodegenerative disease with two pathologicalHow to cite this paper: Yang, D.J., Das, S., Song, L.J., Li, T.X., Yan, J.Q. and Smith, W.W. (2015) LDN-73794 Attenuated LRRK2-Induced Degeneration in a Drosophila Parkinson’s Disease Model. (2015) LDN-73794 Attenuated LRRK2-Induced Degeneration in a Drosophila Parkinson’s Disease Model. The majority of disease-linked LRRK2 mutations are in the GTPase domain or the kinase domain and alter the LRRK2 catalytic activity related to neuronal degeneration [12] [18] [22]-[24]. The most common PD mutation, G2019S-LRRK2, has been reported to increase kinase activity [17][19] [25] [26] and induce neuronal degeneration. Reduction of G2019S-LRRK2 kinase activity protects against neuronal degeneration [18] [23] [27]. The In vitro studies showed that LDN-73794 inhibits LRRK2 kinase activity but has no effect on its GTPase activity. In pharmacological effects of LDN-73794 on LRRK2 in cells and in vivo models are not clear
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