Loss of Function in Key Genes Doesn’t Change Parkinson’s Risk, Study Finds

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Loss or inactivation of a single gene copy of LRRK1 or LRRK2 — LRRK mutations being a common genetic cause of Parkinson’s disease — neither increases the risk nor protects against the disease, a new study showed.

These findings also support the use of kinase inhibitors targeting mutant LRRK2 as a therapeutic option for the disease.

The study, “Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease,” was published in JAMA Neurology.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene — which provides instructions for making a kinase, a type of protein that regulates the functions of many others inside cells — are considered a common genetic cause of Parkinson’s. These LRRK2 mutations typically cause  overactivation of the LRRK2 kinase, leading to increased cell death and disease progression.

Kinase inhibitors  — substances that specifically block this type of enzyme  — have been proposed to treat Parkinson’s disease. However, previous studies in a Parkinson’s mouse model showed that genetic deletion of both LRRK2 gene copies, also known as alleles, together with its homologue (a gene that shares a common ancestral DNA sequence) LRRK1, still resulted in neurodegeneration.

This indicates that Parkinson’s disease can still develop in the absence of LRRK1 and LRRK2  — in other words, in a loss of function (LOF) scenario.

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Because LRRK2 inhibitors are being developed as potential Parkinson’s therapies, it is essential to determine whether LOF variants of LRRK1 and LRRK2 could contribute to the risk of developing the disease.

Researchers designed a large case-control study and screened more than 23,000 people  — 11,095 diagnosed with Parkinson’s and 12,615 healthy participants. Using a technique called next-generation sequencing, they analyzed and compared the frequency of LRRK1 and LRRK2 LOF variants in the two groups.

No significant differences were seen between the frequency of LRRK1 (0.205% vs. 0.139%) and LRRK2 (0.117% vs. 0.087%) LOF variants found in patients and healthy controls, suggesting that LOF variants are not directly associated with Parkinson’s disease.
Cell lines derived from those who carried a single copy of several LRRK2 LOF variants had a 50 percent reduction in LRRK2 protein levels when compared with those who carried two normal LRRK2 gene copies.
These findings indicate that neither LRRK1 nor LRRK2 LOF variants increase or decrease the risk of developing Parkinson’s.
“We add more evidence to support the view that LRRK1 is unlikely to cause disease on its own, and more importantly, that pathogenic LRRK2 variants are likely to act through a gain of function rather than an LOF mechanism to cause PD [Parkinson’s disease],” the researchers wrote.
Because LRRK2 LOF variants do not have a negative impact on a person’s health, they consider the use of kinase inhibitors or allele-specific targeting of mutant LRRK2 as viable treatments for Parkinson’s disease.
“Our results support the expansion of these studies in clinical trials and in cells from LRRK2 variant carriers,” they said.

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