Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration.

Abstract

Therapeutic approaches to slow or block the progression of Parkinson disease (PD) do not exist. Genetic and biochemical studies implicate α-synuclein and leucine-rich repeat kinase 2 (LRRK2) in late-onset PD. LRRK2 kinase activity has been linked to neurodegenerative pathways. However, the therapeutic potential of LRRK2 kinase inhibitors is not clear because significant toxicities have been associated with one class of LRRK2 kinase inhibitors. Furthermore, LRRK2 kinase inhibitors have not been tested previously for efficacy in models of α-synuclein-induced neurodegeneration. To better understand the therapeutic potential of LRRK2 kinase inhibition in PD, we evaluated the tolerability and efficacy of a LRRK2 kinase inhibitor, PF-06447475, in preventing α-synuclein-induced neurodegeneration in rats. Both wild-type rats as well as transgenic G2019S-LRRK2 rats were injected intracranially with adeno-associated viral vectors expressing human α-synuclein in the substantia nigra. Rats were treated with PF-06447475 or a control compound for 4 weeks post-viral transduction. We found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of α-synuclein. Both neurodegeneration and neuroinflammation associated with G2019S-LRRK2 expression were mitigated by LRRK2 kinase inhibition. Furthermore, PF-06447475 provided neuroprotection in wild-type rats. We could not detect adverse pathological indications in the lung, kidney, or liver of rats treated with PF-06447475. These results demonstrate that pharmacological inhibition of LRRK2 is well tolerated for a 4-week period of time in rats and can counteract dopaminergic neurodegeneration caused by acute α-synuclein overexpression.

• Authors: João P L Daher, Hisham A Abdelmotilib, Xianzhen Hu, Laura A Volpicelli-Daley, Mark S Moehle, Kyle B Fraser, Elie Needle, Yi Chen, Stefanus J Steyn, Paul Galatsis, Warren D Hirst, Andrew B West
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 32 Pg. 19433-44 (Aug 07 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26078453 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• 3-(4-(morpholin-4-yl)-7H-pyrrolo(2,3-d)pyrimidin-5-yl)benzonitrile
• Antiparkinson Agents
• Protein Kinase Inhibitors
• Pyrimidines
• Pyrroles
• alpha-Synuclein
• LRRK2 protein, rat
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Protein Serine-Threonine Kinases

Topics

• Animals
• Antiparkinson Agents (pharmacology)
• Dependovirus (genetics)
• Disease Models, Animal
• Female
• Gene Expression Regulation (drug effects)
• Genetic Vectors
• Humans
• Injections, Intraventricular
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
• Male
• Parkinson Disease (drug therapy, genetics, metabolism, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction
• Substantia Nigra (drug effects, metabolism, pathology)
• alpha-Synuclein (genetics, metabolism)