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.
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