Parkinson’s Reversal? A Drug Brings Dying Brain Cells Back to Life

A new study conducted at Stanford University on mice has found that inhibiting an enzyme could save neurons that die due to a specific form of Parkinson’s disease caused by a single gene mutation. The genetic mutation leads to overactivity of the enzyme leucine-rich repeat kinase 2 (LRRK2). Excessive LRRK2 enzyme activity alters the structure of brain cells in a way that disrupts important communication between neurons that produce the neurotransmitter dopamine and cells in the striatum. The striatum is a region deep within the brain that is part of the dopamine system and is involved in movement, motivation, and decision-making.

The results of this study suggest that inhibiting the LRRK2 enzyme could stabilize the progression of symptoms if patients are identified early enough,” said Dr. Suzanne Pfeffer, Emma Pfeiffer Merner Professor of Medical Sciences and Professor of Biochemistry. Researchers can curb LRRK2 overactivity with the MLi-2 LRRK2 kinase inhibitor, a molecule that binds to the enzyme and reduces its activity. Pfeffer added that the genetic mutation is not the only cause of overactive LRRK2 enzyme activity, so treatment with the inhibitor could also help with other forms of Parkinson’s disease or even other neurodegenerative diseases.

Cellular Antennas

About 25% of all Parkinson’s cases are caused by genetic mutations, and the single genetic mutation that makes the LRRK2 enzyme too active is one of the most common. An overactive LRRK2 enzyme causes cells to lose their primary cilia, a cellular appendage that functions like an antenna, sending and receiving chemical messages. A cell that has lost its primary cilia is like a cell phone when the network is down—no messages are coming in and no messages are going out.

In a healthy brain, many messages are sent back and forth between dopamine neurons in a region of the brain called the substantia nigra and the striatum. These cellular “conversations” are possible because the axons of the dopamine neurons, which are tubular extensions protruding from the cell body, extend to the striatum to communicate with neurons and glial cells that support nerve function.

An important communication that is disrupted by excessive LRRK2 enzyme activity occurs when dopamine neurons are stressed and send out a signal called Sonic Hedgehog (named after the cartoon character) in the striatum. In a healthy brain, this causes certain neurons and astrocytes, a type of glial cell, in the striatum to produce proteins called neuroprotective factors. As the name suggests, these proteins help protect other cells from dying. When LRRK2 enzyme activity is too high, many of the striatum cells lose their primary cilia—and with them their ability to receive signals from the dopamine neurons. This disruption of Sonic Hedgehog signaling means that the necessary neuroprotective factors are not produced.

Restored Cilia were Unexpected

The aim of the study was to test whether the MLi-2 LRRK2 kinase inhibitor can reverse the effects of excessive LRRK2 enzyme activity. Since the neurons and glial cells examined in this study were fully mature and no longer multiplying through cell division, the researchers were initially unsure whether the cilia could grow back. Using mice with the genetic mutation that causes LRRK2 overactivity and symptoms consistent with early-onset Parkinson’s disease, the scientists first tried administering the inhibitor to the mice for two weeks. No changes in brain structure, signal transmission, or dopamine neuron viability were observed.

Recent findings about neurons involved in regulating the circadian rhythm, i.e., the sleep-wake cycle, inspired the researchers to try again. The primary cilia of these cells, which also stopped dividing, grew and shrunk every 12 hours. The team decided to investigate what happens when mice with overactive LRRK2 enzyme take the inhibitor over a longer period of time. Pfeffer described the results as “astonishing.” After three months of taking the inhibitor, the percentage of striatum neurons and glial cells typically affected by the overactive LRRK2 enzyme and exhibiting primary cilia in mice with the genetic mutation was no longer distinguishable from that in mice without the genetic mutation. Similar to how our ability to send and receive text messages is restored when we move from an area with poor cell phone reception to an area with good reception, the increase in primary cilia restored communication between the dopamine neurons and the striatum.

Investigation of Other Forms of Parkinson’s Disease

In response to hedgehog signals from dopamine neurons, the striatal neurons and glial cells released neuroprotective factors in the same amount as in the brains of mice without the genetic mutation. The hedgehog signals from the dopamine neurons decreased, suggesting that they were less stressed. In addition, the density of dopamine nerve endings in the striatum doubled, indicating initial recovery of the dying neurons. “These results suggest that it may be possible not only to stabilize the condition of Parkinson’s patients, but even to improve it,” said Pfeffer. The earliest symptoms of Parkinson’s disease appear about 15 years before the onset of tremors. These include loss of smell, constipation, and a form of sleep disorder in which those affected act out their dreams while sleeping, according to Pfeffer. She said the hope is that people with the LRRK2 gene mutation can start treatment that inhibits the enzyme as early as possible. The next step for the research team is to test whether other forms of Parkinson’s disease that are not associated with the LRRK2 gene mutation could also benefit from this type of treatment.