Parkinson's Disease Gene Required for Healthy Dopamine Neurons

A gene that is commonly linked to late-onset Parkinson’s disease is now known to be necessary for the function of healthy dopamine neurons, according to a new study published by Neuron.

For a decade, researchers have known that the gene LRRK2 is involved with Parkinson’s disease, but the specific role it plays in the condition and how it affects healthy brain function were previously unknown.

In the new study, the authors discovered that the survival of dopamine-containing neurons is contingent on LRRK. These neurons are the most affected by Parkinson’s disease, according to the authors.

The authors said these new findings could result in improved treatments for Parkinson’s disease.

“Since its discovery, researchers have been trying to define LRRK2 function and how mutations may lead to Parkinson’s disease,” said Beth-Anne Sieber, PhD, program director at the National Institute for Neurological Disorders and Stroke. “The findings in this paper emphasize the importance of understanding the normal role for genes associated with neurodegenerative disorders.”

In the brain, LRRK2 is found with LRRK1, a closely related protein. An LRRK2 mutation will eventually result in Parkinson’s disease during aging; however, LRRK2 mutation will not cause dopamine-producing neurons to die. The authors hypothesize that LRRK1 may have a compensatory role, according to the study.

“Parkinson’s-linked mutations such as LRRK2 have subtle effects that do not produce symptoms until late in life. Understanding the normal function of these types of genes will help us figure out what has gone wrong to cause disease,” said senior author Jie Shen, PhD.

Included in the study were mice that lacked LRRK1 and LRRK2. The authors discovered a loss of dopamine-containing neurons in the areas of the brain related to Parkinson’s disease, according to the study.

Upon examining the affected brain cells, the authors discovered buildup of the α-synuclein protein, which is a marker of both Parkinson’s disease and Alzheimer’s disease.

The authors also noted that more dopamine-containing neurons began to show signs of apoptosis, suggesting the proteins are important for healthy brain cells.

“Our findings show that LRRK is critical for the survival of the populations of neurons affected by Parkinson’s disease,” Dr Shen said.

Although a lack of LRRK1 and LRRK2 did not affect brain size or cells in the areas unrelated to Parkinson’s disease, the mice had lower weight and a shorter lifespan. These factors prevented the authors from observing other symptoms and conducting a long-term analysis on how the deletion affects the brain, according to the study.

The authors found that the most common LRRK2 mutation is thought to increase the protein’s activity. This has resulted in many therapies designed to inhibit LRRK2 activity, according to the authors.

The investigators are working to create mice models with LRRK1 and LRRK2 removed in dopamine-containing neurons of the brain, which is expected to result in a longer-term analysis of behavioral changes while avoiding adverse events, according to the study.

“The fact that the absence of LRRK leads to the death of dopamine-containing neurons suggests that the use of inhibitory drugs as a treatment for Parkinson’s disease might not be the best approach,” Dr Shen concluded.