Details

Autor(en) / Beteiligte

• Daher, João P.L.
• Abdelmotilib, Hisham A.
• Hu, Xianzhen
• Volpicelli-Daley, Laura A.
• Moehle, Mark S.
• Fraser, Kyle B.
• Needle, Elie
• Chen, Yi
• Steyn, Stefanus J.
• Galatsis, Paul
• Hirst, Warren D.
• West, Andrew B.

Titel

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

Ist Teil von

• The Journal of biological chemistry, 2015-08, Vol.290 (32), p.19433-19444

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. Background: LRRK2 kinase activity has been implicated in Parkinson disease (PD). Results: LRRK2 kinase inhibition attenuated neurodegeneration in LRRK2 transgenic and wild-type rats. Conclusion: Chronic inhibition of LRRK2 kinase activity is well tolerated in rats and provides neuroprotection from α-synuclein overexpression. Significance: These results warrant further studies that test the therapeutic potential of LRRK2 kinase inhibitors in additional PD models.