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

TY - JOUR

T1 - Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson’s disease–linked LRRK2-mutant mice

AU - Jaimon, Ebsy

AU - Lin, Yu En

AU - Tonelli, Francesca

AU - Antico, Odetta

AU - Alessi, Dario R.

AU - Pfeffer, Suzanne R.

N1 - Publisher Copyright: © 2025 The Authors, some rights reserved.

PY - 2025/7/1

Y1 - 2025/7/1

N2 - Parkinson’s disease is associated with activating mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which suppresses primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum. As a result, there is a decrease in the production of neuroprotective glial cell line–derived neurotrophic factor (GDNF) and neurturin (NRTN), which normally support the viability of dopaminergic neurons. MLi-2 is a brain-penetrant, selective, and now experimental inhibitor of LRRK2. Here, we found that dietary administration of MLi-2 to young LRRK2-mutant mice for 3 months restored primary cilia formation and Hedgehog signaling in both cholinergic and parvalbumin interneurons and astrocytes. The treatment also restored the Hedgehog-responsive expression of Gdnf and Nrtn in the neurons. Cilia were also restored on cholinergic neurons of the pedunculopontine nucleus, where their loss correlates with severity of motor impairment in patients. Furthermore, MLi-2 increased the density of fine striatal dopaminergic processes and decreased the amount of stress-associated Sonic Hedgehog RNA expression in nigral dopaminergic neurons. Thus, pathogenic LRRK2-driven cilia loss is reversible in postmitotic neurons and astrocytes, which suggests that early administration of specific LRRK2 inhibitors may therapeutically benefit patients.

AB - Parkinson’s disease is associated with activating mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2), which suppresses primary cilia formation in cholinergic and parvalbumin interneurons and astrocytes in the striatum. As a result, there is a decrease in the production of neuroprotective glial cell line–derived neurotrophic factor (GDNF) and neurturin (NRTN), which normally support the viability of dopaminergic neurons. MLi-2 is a brain-penetrant, selective, and now experimental inhibitor of LRRK2. Here, we found that dietary administration of MLi-2 to young LRRK2-mutant mice for 3 months restored primary cilia formation and Hedgehog signaling in both cholinergic and parvalbumin interneurons and astrocytes. The treatment also restored the Hedgehog-responsive expression of Gdnf and Nrtn in the neurons. Cilia were also restored on cholinergic neurons of the pedunculopontine nucleus, where their loss correlates with severity of motor impairment in patients. Furthermore, MLi-2 increased the density of fine striatal dopaminergic processes and decreased the amount of stress-associated Sonic Hedgehog RNA expression in nigral dopaminergic neurons. Thus, pathogenic LRRK2-driven cilia loss is reversible in postmitotic neurons and astrocytes, which suggests that early administration of specific LRRK2 inhibitors may therapeutically benefit patients.

UR - https://www.scopus.com/pages/publications/105010287242

UR - https://datadryad.org/dataset/doi:10.5061/dryad.q2bvq83tn

U2 - 10.1126/scisignal.ads5761

DO - 10.1126/scisignal.ads5761

M3 - Article

C2 - 40591712

AN - SCOPUS:105010287242

SN - 1945-0877

VL - 18

JO - Science Signaling

JF - Science Signaling

IS - 893

M1 - eads5761

ER -