NEW YORK (Reuters Health) - Researchers have evidence tying autosomal-dominant, late-onset Parkinson’s disease (PD) to several mutations in a gene encoding a large, multifunctional protein -- LRRK2 (leucine-rich repeat kinase 2). The gene is located in a previously identified susceptibility region, PARK8, on chromosome 12.
“This is a relatively common cause for dominantly inherited late-onset PD,” Dr. Thomas Gasser from University of Tubingen in Germany told Reuters Health. “As far as we can tell now, it is responsible in about 10% to 15% of cases, which is much more common than [mutations in] alpha-synuclein,” he added, which have previously been linked to familial PD.
According to a report in the November 18th issue of the journal Neuron, Dr. Gasser and colleagues identified six LRRK2 mutations (five missense and one putative splice site mutation) in 34 families with autosomal-dominant PD.
These LRRK2 mutations segregated with disease and were not found in more than 1000 healthy controls or 300 individuals with sporadic PD.
Autopsy findings in six affected individuals within two large families showed neuronal loss and gliosis in the substantia nigra, which is the likely pathologic substrate of parkinsonism, the team notes.
LRRK2 mutations “seem to be associated with a particularly wide spectrum of pathologic changes,” Dr. Gasser said, “including those of typical PD, Lewy body dementia and also PSP” -- that is, progressive supranuclear palsy-like pathology.
“We think that this is telling us that the gene product is at a crucial and central point of the neurodegenerative process, and that the specific pathologic ‘finger-print’ in a given patient is determined by modifying factors,” he said.
The researchers hypothesize that LRRK2 “may be responsible for the phosphorylation of both alpha-synuclein and tau; its kinase activity could be a key event in the accumulation and aggregation of these unfolded proteins within degenerating neurons,” they suggest.
In an editorial, Dr. Jie Shen from Harvard Medical School in Boston says, “it will be of particular interest to determine whether and how the LRRK2 protein and its putative GTPase and tyrosine kinase activities interact with other gene products or pathways thus far implicated in familial parkinsonism.”
Source: Neuron 2004;44:575-576,601-607. [ Google search on this article ]
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