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We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like …