A perspective article summarizes what researchers have learned so far on the role of LRRK2 mutations in the development of Parkinson’s disease, and recommends the enzyme as a target for therapy development.
Although the vast majority of Parkinson’s cases are idiopathic, or of unknown cause, LRRK2 mutations — the leading genetic cause of this disease — account for about 1 to 2 percent of all cases. Mutations in this gene increase the risk of developing Parkinson’s due to an LRRK2-increased risk of neuronal death.
About 20 LRRK2 mutations have been linked with the disease, and its incidence can be higher in some populations such as the Ashkenazi Jews and North African Berbers.
The LRRK2 gene codes for the enzyme leucine-rich repeat kinase 2 (LRKK2), a protein that modifies other proteins’ activities, including signaling, replication, and gene expression.
All LRRK2 disease-causing mutations lead to higher LRKK2 enzyme activity; as such, researchers believe that inhibiting or blocking its activity can be used as a potential therapeutic target.
In fact, two LRRK2 inhibitors are currently being evaluated to treat Parkinson’s in two Phase 1 trials. The experimental therapies, called DNL-201 and DNL-151, are being developed by Denali Therapeutics. So far, DNL201 has stopped an average 90 percent of LRRK2 kinase activity at its highest concentration. When the drug’s levels dropped to the lowest concentration, it still inhibited on average 50 percent of such activity.
Studying the effects of LRRK2 mutations also provides an opportunity to better understand how Parkinson’s disease unravels, the study notes.
Recent advances support that LRRK2 modifies a group of proteins, called Rab GTPases, that regulate diverse cellular processes.
These proteins play important roles in immune responses and vesicular trafficking — the transport and recycling of materials inside the cell through a system of vesicles.
Disruption of RAB-related transport may also promote accumulation of alpha-synuclein aggregates inside neurons, a hallmark of Parkinson’s disease.
LRRK2 is also thought to be linked to inflammation, a process that plays an important part in disease development. LRRK2 is highly expressed in several immune system cells, including macrophages, monocytes, and neutrophils.
“Research indicates that, in early life, increased LRRK2 activity may protect against opportunistic pathogenic infection but then later increases the risk of developing Parkinson’s disease,” the researchers write.
LRRK2-associated Parkinson’s closely resembles idiopathic disease in terms of its late age of onset and symptoms. But several factors seem to influence the ability of LRRK2 mutations to cause disease, including age and the type of mutation.
People carrying some types of mutations, such as G2019S, may never develop Parkinson’s, while nearly all of those bearing the R1441G mutation eventually will.
One case report in twins carrying the same LRRK2 mutation found only one developed Parkinson’s. This highlights the importance of environmental factors and lifestyle (smoking, exercise, diet), as well as the gut microbiome and infection in the development of LRRK2-dependent Parkinson’s.
“However, for now, the most exciting question will be whether LRRK2 inhibitors have disease-modifying effects in PD patients with LRRK2 mutations,” the researchers wrote.
The authors stress that preclinical studies in animal models indicate potential toxicity of LRRK2 inhibitors to the lungs and kidneys, and recommend special attention be taken to monitor toxicity in these organs in human clinical trials.
Given the role of LRRK2 in fighting infections, it will also be important to establish whether blocking LRRK2 increases the risk of opportunistic infections. But, overall, the scientists believe that “LRRK2 is a possible therapeutic target for Parkinson’s disease.”
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