Parkinson’s gene affects more people than previously thought

New research finds that a gene previously thought to affect only a small percentage of Parkinson’s disease cases actually affects many more. The findings mean that treatments that are being developed for a small number of people may, in fact, benefit many more.
lewy bodies
Parkinson’s disease is characterized by Lewy bodies (shown here as red dots), which accumulate inside dopamine neurons.

Almost 1 million people in the United States and nearly 10 million people across the world live with Parkinson’s disease.

According to the National Institutes of Health (NIH), 15 percent of those living with Parkinson’s have a hereditary form of the disease.

Such hereditary forms of the condition are often down to mutations in several genes. The LRRK2 gene is one of them.

Responsible for creating a protein called dardarin — which has important roles in maintaining the structural health of cells — LRRK2 has been found to play a key role in late-onset Parkinson’s disease, which is the most widespread form of the condition.

More specifically, 100 mutations of this gene have been found in familial cases of Parkinson’s. Overall, 3–4 percent of Parkinson’s cases have been linked with mutations in this gene.

But now, researchers have made a discovery that suggests that LRRK2 is implicated in far more cases than previously thought.

It isn’t just the mutated version of the gene that may cause Parkinson’s, and it isn’t just people with a family history of the disease who are affected by this gene, suggests the new study.

Dr. J. Timothy Greenamyre, chief of the Movement Disorders Division at the University of Pittsburgh Medical Center in Pennsylvania, is the senior author of the study, which was published in the journal Science Translational Medicine.

LRRK2 activity leads to toxic protein buildup

Dr. Greenamyre and colleagues used an innovative technique called “proximity ligation assay” to detect the activity of LRRK2.

They designed a molecular “beacon” that they attached to the LRRK2 protein. If the protein was active, it would glow, enabling the researchers to see in which brain cells LRRK2 was active.

The researchers applied the technique to study the postmortem brain tissues of people who had had Parkinson’s but who did not have a mutation of the gene, and they compared them with those of healthy brains.

Dr. Greenamyre and team found that LRRK2 was overactive in the brains of people who had had the disease, but not in healthy brain tissue. Namely, the activity of this protein was “aberrantly increased” in dopamine neurons, which are the most commonly damaged neurons in Parkinson’s.

Additionally, the researchers designed a mouse model of Parkinson’s and examined the activity of LRRK2 in the rodents’ brains.

They found that LRRK2 activity inhibited cells from carrying out their normal “cleaning” activity, in which they would clear up the excessive buildup of the brain protein alpha-synuclein.

Accumulation of alpha-synuclein leads to the formation of Lewy bodies, which are a pathological hallmark of Parkinson’s and some forms of dementia.

Moreover, the researchers administered an LRRK2-inhibitor to the rodents, which blocked the accumulation of the pathological protein.

Roberto Di Maio — an assistant professor in Dr. Greenamyre’s laboratory and the study’s lead author — explains the findings, saying, “LRRK2 ties together both genetic and environmental causes of Parkinson’s, as we were able to show that external factors like oxidative stress or toxins can activate LRRK2, which can in turn cause Lewy bodies to form in the brain.”

This discovery is extremely consequential for Parkinson’s disease because it suggests that therapies currently being developed for a small group of patients may benefit everybody with the disease.”

Dr. J. Timothy Greenamyre

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