MIAMI BEACH—The newest gene for Parkinson’s disease is shaping up to be perhaps the most important of all, at least if importance is judged by how many patients carry it. Called LRRK2, it appears to account for about 6% of all cases of autosomal dominant Parkinson’s disease, as well as a smaller but still important fraction of sporadic cases, and according to the latest news, even some cases of early-onset disease. The protein—Lrrk2—is a kinase that may be at the head of a well-known signaling pathway that controls apoptosis, and in its mutant form it appears to gain a toxic function. The protein is a promising target for drug development, and at least one clinical trial of an inhibitor that may reduce Lrrk2 activity is now under way.

A COMMON CAUSE

The news on LRRK2 has been emerging rapidly since the publication in November 2004 of two papers that identified LRRK2 as the gene at the PARK8 locus, first linked to autosomal dominant disease in 1997 by researchers in Japan. These papers identified the gene, located on chromosome 12q, in families from the United States, Norway, Ireland, Poland, and the Basque region of Spain. Further studies indicate it is also found elsewhere in Europe and in North Africa. “It is by far the most common genetic form of Parkinson’s disease,” according to Matthew Farrer, PhD, of the Mayo Clinic in Jacksonville, Florida, who was lead investigator on several studies presented at the 57th Annual Meeting of the American Academy of Neurology.

Just how common it is becomes clearer as more populations are studied. In the published reports, LRRK2 mutations appear to account for between 4% and 8% of all familial late-onset disease. Its prevalence among the general Parkinson’s disease population is less clear, but a study reported at the meeting indicated it may be responsible for about 2% of sporadic Parkinson’s disease as well. Jan Aasly, MD, a movement disorders specialist at Saint Olav’s Hospital in Trondheim, Norway, reported that of his 435 patients with Parkinson’s disease, nine—or just over 2%—tested positive for a single mutation in the LRRK2 gene, while none of 624 unaffected controls did.

The mean age at onset for these patients was 53, with a range from 43 to 70, and all presented as sporadic Parkinson’s disease cases. The range of presentations and features “is what you would expect in a large Parkinson’s disease practice,” said Dr. Aasly, with tremor as the initial symptom in six patients, bradykinesia in three, and dystonia in one. All were responsive to levodopa and were susceptible to levodopa-induced dyskinesias. One patient received and was successfully treated with subthalamic nucleus deep brain stimulation. The clinical course for these patients was “not more benign” than that for those without mutation, he said, although in this small sample he has seen little or no dementia.

INHERITANCE PATTERN

The inheritance pattern of all LRRK2 mutations found to date appears to be autosomal dominant with reduced penetrance, according to Mathias Toft, MD, also of the Mayo Clinic, Jacksonville, who reported on a study of six families from Europe and the US. “The penetrance is highly age dependent,” he said, with only about 20% of individuals affected by the age of 50, but over 80% older than 70. Interestingly, the two individuals with the latest and earliest onset were from the same family: a mother at age 78 and a son at age 39. Genetic analysis of the region surrounding the gene shows that the families all share a common, very small haplotype, indicating the presence of a founder effect from a very old mutation.

However, Christine Klein, MD, of Luebeck University in Germany, noted it may be too early to limit LRRK2’s role in Parkinson’s disease to late-onset patients. Speaking from the audience in the same session, she reported that two in a series of 100 of her patients with early-onset Parkinson’s disease had LRRK2 mutations, indicating a potential role for the gene beyond late-onset disease. The two had different mutations and very different clinical courses, with one progressing very slowly, and one, very rapidly. “I think it is too early to speculate about the phenotypic spectrum” of LRRK2 mutations, she said. “There is a big need for very large-scale studies.”

OVERACTIVE KINASE MAY BE A TARGET FOR DRUG THERAPY

In total, six different mutations within the gene’s 51 exons have been discovered among the various populations studied, and these have been linked to different regions of the protein. The gene’s size makes sequencing difficult and time-consuming, and therefore the current estimates of the prevalence of gene mutations are likely to be too low. To date, the most common is the G2019S mutation, found in most of the groups studied, though not in Basque patients. Dr. Toft said that this mutation by itself may account for about 1% of all autosomal dominant Parkinson’s disease.

This mutation occurs within the kinase domain of the protein, and the affected codon is conserved not only among different species but also among different kinases. Therefore, said Dr. Toft, “it has to have a crucial function.” He suggested that the likely mode of action was a toxic gain of function. Mutations within this domain in related kinases have been shown to cause increased kinase activity, and molecular modeling appears to support this idea for Lrrk2 as well.

Dr. Farrer speculated that the protein acts within a signaling cascade—possibly the well-studied JNK pathway that controls apoptotic cell death. His group, which includes Dr. Toft, is testing this hypothesis, although it is difficult, he said, since there are not yet any known substrates. “There is some evidence, but we haven’t nailed it yet.”

Meanwhile, a clinical trial of the mixed-lineage inhibitor CEP-1347, which targets this kind of kinase, is under way in Parkinson’s disease. Sponsored by Cephalon and coordinated by the Parkinson Study Group, the trial began before discovery of the gene, based on primate data showing that inhibition of the JNK pathway might help save cells from apoptosis. “If LRRK2 G2019S mutations actually cause overactivation of this pathway, these drugs may actually be efficacious in patients who are genetically diagnosed” but have not yet developed clinical disease, said Dr. Farrer. “That would be marvelous, since we could stop it before they get it.”

NR

—Richard Robinson

Suggested Reading
Aasly JO, Toft M, Fernandez-Mata I, et al. Clinical features of LRRK2-associated Parkinson’s disease in central Norway. Ann Neurol. 2005;57:762-765.
Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44:595-600.
Toft M, Mata IF, Kachergus JM, et al. LRRK2 mutations and Parkinsonism. Lancet. 2005;365:1229-1230.
Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601-607.

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