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In a new study published in Science Signaling titled, “Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinson’s linked-LRRK2 mutant mice,” researchers from Stanford University and University of Dundee have shown that inhibition of a specific enzyme may rescue neurons that are dying due to a type of Parkinson’s disease that is caused by a single genetic mutation in a mouse model.
About 25% of Parkinson’s disease cases are caused by genetic mutations. Activating mutations in leucine-rich repeat kinase 2 (LRRK2) is one of the most common Parkinson’s associated mutations. Overactive LRRK2 leads to the loss of primary cilia in neurons which disrupts crucial communication that makes the neurotransmitter dopamine.
Overactive LRRK2 can be mitigated using MLi-2 LRRK2 kinase inhibitor. Given that the genetic mutation is not the only mechanism of overactive LRRK2, the inhibitor treatment might help with other types of neurodegenerative diseases.
“Findings from this study suggest that inhibiting the LRRK2 enzyme could stabilize the progression of symptoms if patients can be identified early enough,” said Suzanne Pfeffer, PhD, professor of biochemistry at Stanford and corresponding author of the study.
In a healthy brain, many messages are sent between dopamine neurons in the substantia nigra and the striatum. This signaling is possible because dopamine neuron axons reach the striatum to communicate with neurons and glia.
Dopamine neurons release Sonic Hedgehog (Shh), a signaling protein critical for brain development and function, which plays a key role in cell growth, differentiation, and the formation of neural circuits. In a healthy brain, Shh causes certain neurons and astrocytes in the striatum to produce proteins called neuroprotective factors. Overactivation of LRRK2 disrupts Shh signaling and lowers neuroprotective factor production.
Results showed that three month-dietary administration of MLi-2 LRRK2 kinase inhibitor to mice restored primary cilia and Shh responsive production of neuroprotective factors. In addition, indicators of the density of dopamine nerve endings within the striatum doubled, suggesting an initial recovery for neurons that had been in the process of dying. The findings potentially offer an avenue to improve, not just stabilize, the condition of patients with Parkinson’s disease.
“Many kinds of processes necessary for cells to survive are regulated through cilia sending and receiving signals,” Pfeffer explained. “We think that when cells have lost their cilia, they are also on the pathway to death because they need cilia to receive signals that keep them alive.”
The earliest symptoms of Parkinson’s disease begin about 15 years before a patient notices a tremor. Pfeffer said the hope is that people who have the LRRK2 genetic mutation can start a treatment that inhibits the enzyme as early as possible.
Looking ahead, the research team will test whether other forms of Parkinson’s disease not associated with the LRRK2 genetic mutation could benefit from this type of treatment.
“We are so excited about these findings. They suggest this approach has great promise to help patients in terms of restoring neuronal activity in this brain circuit,” Pfeffer said. “There are multiple LRRK2 inhibitor clinical trials underway, and our hope is that these findings in mice will hold true for patients in the future.”