Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson’s linked-LRRK2 mutant mice

Parkinson’s disease-associated, activating mutations in Leucine Rich Repeat Kinase 2 (LRRK2) block primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum, decreasing the production of GDNF and NRTN neuroprotective factors that normally support dopaminergic neuron viability.  We show here that 3 month-dietary administration of the MLi-2 LRRK2 kinase inhibitor restores primary cilia and the Hedgehog-responsive production of neuroprotective GDNF and NRTN by these neurons; cilia are also restored on cholinergic neurons of the pedunculopontine nucleus.  Importantly, we detect recovery of striatal dopaminergic processes and decreased stress-triggered Hedgehog signaling by nigral dopaminergic neurons.  Thus, pathogenic LRRK2-driven cilia loss is reversible in post-mitotic neurons and astrocytes, which suggests that early administration of specific LRRK2 inhibitors may have significant therapeutic benefit for patients in the future., Reagents
MLi-2 LRRK2 inhibitor was synthesized by Natalia Shpiro (MRC Reagents and Services, University of Dundee) and was first described to be a selective LRRK2 inhibitor in previous work (M.J Fell et al., 2015). For the MLi-2 in diet study, rodent diet containing MLi-2 at 360 mg per Kg was manufactured by Research diets, Inc.
Research standards for animal studies
Mice were maintained under specific pathogen-free conditions at the University of Dundee (UK). All animal experiments were ethically reviewed and conducted in compliance with the Animals (Scientific Procedures) Act 1986 and guidelines established by the University of Dundee and the U.K. Home Office. Ethical approval for animal studies and breeding was obtained from the University of Dundee ethical committee, and all procedures were performed under a U.K. Home Office project license. The mice were group-housed in an environment with controlled ambient temperature (20–24°C) and humidity (45–55%), following a 12-hour light/12-h..., , # **Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson’s linked-LRRK2 mutant mice**

[https://doi.org/10.5061/dryad.q2bvq83tn](https://doi.org/10.5061/dryad.q2bvq83tn)

Author/Principal Investigator Information

Name: Suzanne R. Pfeffer

ORCID: 0000-0002-6462-984X

Institution: Stanford University

Address: Beckman

Center Room B413

279 Campus DriveStanford, California 94305-5307

Email: [[e-mail]](mailto:[e-mail])

Author/Principal Investigator Information

Name: Dario R. Alessi

ORCID: 0000-0002-2140-9185

Institution: MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, United Kingdom

Address: MRC PPU

Sir James Black Centre

School of Life Sciences

University of Dundee

Dow St.

Dundee DD1 5EH

Email: [[e-mail]](mailto:[e-mail])

Author/Associate or Co-investigator Information

Name: Ebsy Jaimon

ORCID: 0000-0001-6845-2095

Institution: Stanford University

Address...,