Therapies Targeting LRRK2 Gene Could Benefit Broad Population of Parkinson’s Patients, Study Finds

Therapies Targeting LRRK2 Gene Could Benefit Broad Population of Parkinson’s Patients, Study Finds

The LRRK2 gene may play an important role in nonhereditary Parkinson’s disease, not just the familial form as previously thought, researchers at the University of Pittsburgh School of Medicine​ have discovered.

“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,” J. Timothy Greenamyre, MD, PhD, the study’s senior author, said in a press release. Greenamyre is the Love Family Professor of Neurology at Pitt’s School of Medicine, chief of the movement disorders division at the University of Pittsburgh Medical Center, and director of the Pittsburgh Institute for Neurodegenerative Diseases.

These new findings were reported in the study, “LRRK2 activation in idiopathic Parkinson’s disease,” published in Science Translational Medicine.

Parkinson’s disease is a chronic and progressive neurodegenerative condition caused by the loss of dopamine-producing neurons in the substantia nigra, a brain region involved in the control of voluntary movements. It is estimated to affect 1 million people in the U.S. and up to 10 million worldwide.

There are two basic types of Parkinson’s: the familial hereditary form of the disease, which is associated with genetic mutations that make individuals more prone to develop Parkinson’s; and the idiopathic nonhereditary form of the disease, where the causes are unknown.

Genetic mutations in the leucine-rich repeat kinase 2 (LRRK2) gene — which provides instructions for making a kinase, a type of protein that regulates the function of many others — that cause an overactivation of the protein have been associated with the familial form of Parkinson’s.

However, researchers still do not know if the normal, nonmutated LRRK2 gene could also play a role in the idiopathic form of the disease.

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To answer this, investigators set out to analyze the activity of LRRK2 in postmortem brain samples from patients with idiopathic Parkinson’s, who did not have genetic mutations in LRRK2, and healthy individuals from the same age group used as controls.

But studying LRRK2 is difficult because its levels in the brains of Parkinson’s patients are extremely low and hard to detect.

To overcome this, Greenamyre’s team took advantage of a technique called proximity ligation assay, which works by attaching special fluorescent molecules to LRRK2 that glow red when the protein is active, allowing researchers to spot them under a microscope.

Investigators found that LRRK2 activity was increased in dopamine-producing neurons from the substantia nigra of patients with idiopathic Parkinson’s, in comparison with healthy controls.

Interestingly, they observed the same trend in two different rat models of the disease, suggesting that LRRK2 overactivity seems to be important not only for patients with genetic mutations in LRRK2, but also for other individuals with the idiopathic form of the disease.

They then found that LRRK2 activity is linked to alpha-synuclein — a protein that accumulates inside nerve cells, producing small structures called Lewy bodies — that is considered a hallmark of Parkinson’s disease.

Using an animal model of Parkinson’s, they discovered that LRRK2 activation actually blocks the mechanism cells use to clear excessive alpha-synuclein, eventually leading to an abnormal buildup of the protein inside nerve cells.

Researchers then treated these animals with an investigational treatment intended for patients with familial Parkinson’s that works by blocking LRRK2 activity. Remarkably, they observed that the therapy was able to prevent both the accumulation of alpha-synuclein and the formation of Lewy bodies inside nerve cells.

These findings show that, regardless of genetic mutations, the LRKK2 gene plays a role in both types of Parkinson’s disease, indicating that LRRK2 inhibitors may be useful to treat patients with the idiopathic or familial form of the disease.

“We believe that LRRK2 inhibitors may be beneficial not only for the 3 to 4% of people with [Parkinson’s disease] who carry LRRK2 mutations but also for [idiopathic Parkinson’s disease] patients who do not carry LRRK2 mutations,” the authors wrote in the study.

In the future, Greenamyre’s team aims to investigate how LRRK2 overactivity can be prevented, as well as determining the underlying mechanisms that cause its activation in Parkinson’s patients.

3 comments

  1. Reni Winter-Evans says:

    I have two different LRRK2 variants but only extremely mild symptoms and as yet no diagnosis. Perhaps researchers would do well to seek people with the mutation and extremely mild symptoms – so mild that their PCP might not even want to refer them to a neurologist – who are perhaps in Stage 1 or less and would perhaps have the right LRRK2 protein levels. Anyone interested in research with someone with BOTH the G2019s AND G2385R please contact me. I have them both and numerous other variants in the SNCA, UCHL, LOC10, STAP1, NUCKS (Park16) and MAPT. I want to do whatever I can to help find an early diagnosis, treatment and cure!

  2. Joann Rubino says:

    I was diagnosed with Parkinson’s in 2011 because of a slight tremor in my right hand I now have a Trevor in my right leg and left hand by writing a small and it seems like my fine motor skills are starting to be affected however I continue to lead a normal life and run a business if there are any trials then I might participate in I might be interested in knowing about them. I am not on any medication

  3. David Skutnik says:

    Just like these individuals I also have been experiencing simmiliar symptoms. We’re reaching out to you to let us participate in research studies. Speaking for myself I am willing to sign any release to participate in a study. Research with rats is great. Give me the shot to see if it helps.

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