An oral, experimental drug has shown potential for reversing early Parkinson’s disease (PD) in people with a particular genetic mutation, preclinical research suggests.
The study, in Science Signaling, found that an inhibitor of the Leucine-Rich Repeat Kinase (LRRK)2 called MLi-2 could prevent a core PD process in young mice with the genetic variant. MLi-2 reversed a hallmark of the disease on neurons and restored neuron-protecting pathways. The hope is that it could one day offer an early treatment route for patients in whom the disease is related to mutations in the gene encoding LRRK2.
Interestingly, earlier research by the same researchers did not see the benefits when mice were given food containing MLi-2 for two weeks. It was only after seeing that multiple LRRK2 inhibitor clinical trials were underway that they fed it to the mice for longer, whereupon the benefits appeared.
“Our findings indicate that this approach has clinical potential, and the study exemplifies the importance of temporal considerations in translational research,” reported Ebsy Jaimon, PhD, from Stanford University, and co-workers.
Around a quarter of PD cases relate to genetic mutations, one of which is mutations on the gene encoding LRRK2. Mutation in the LRRK2 protein disrupts the formation of hair-like, cilia protrusions in neurons and astrocyte cells in the striatum area of the brain.
Losing cilia leads to a drop in the protective factors named GDNF and neurturin and leaves neurons susceptible to cell death.
Jaimon and team found that dietary supplementation with the LRRK2 inhibitor for three months treated a cellular deficit related to the disease that was caused by the LRRK2 mutation. The researchers added MLi-2, which can penetrate the brain, to the diet of mice with a type of PD associated with mutations in the kinase LRRK2.
After beginning to feed the animals at 10 weeks of age, when cilia are deficient, they found that that MiLi-2 could restore the formation of cilia in the striatum of the brains of the young mice. Dietary supplantation of MLi-2 for three months restored cilia formation in neurons and astrocytes in the striatum. In addition, it restarted the formation of cilia in neurons in the pedunculopontine nucleus, where their loss relates with movement issues in PD patients.
MLi-2 also restored the activity of the Hedgehog signaling pathway, and this increased the expression of the genes that encode the neuroprotective factors GDNF and neurturin.
“Fine dopaminergic processes in the striatum returned to wild-type density, and dopamine neurons of the substantia nigra synthesized less Sonic Hedgehog (Shh) RNA, suggestive of less stress.
“All these changes are encouraging for patients who may be eligible for LRRK2 inhibitor therapy in the future.”
