Several pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2; PARK8) gene recently have been identified in familial and sporadic parkinsonism.
These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2.
Therefore, the LRRK2 mutation has a relatively high frequency in the AJ population, is not fully penetrant for parkinsonism in the elderly, and does not appear to be commonly associated with late-onset dementia.
We have identified Family SK where Lrrk2G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology.
Understanding the molecular function of the LRRK2 protein and its associated pathways might elucidate the switch between Lewy body pathology and neurofibrillary tangles, and holds promise for prospective therapeutics that might slow or halt progression of many forms of parkinsonism.
Moreover, mutations in LRRK2 known to cause parkinsonism are associated not only with dopaminergic neuronal degeneration, but also with the accumulation of synuclein, tau, neither, or both proteins.
All patients carrying the LRRK2G2019S exhibited typical levodopa-responsive parkinsonism, and severe levodopa-induced dyskinesia was observed in the patient carrying the LRRK2 and parkin mutations.