Genetics of Parkinson's disease: LRRK2 on the rise

Abstract

Our view of the pathogenic mechanisms of Parkinson's disease has greatly changed over the past decade with the identification of several genes implicated in Mendelian forms of this disorder (Corti et al. , 2005; Gasser et al. , 2005). Parkin, DJ-1 and PINK1 are responsible for autosomal recessive forms, usually with early onset, that are not associated with Lewy bodies. α-Synuclein was considered to be the major gene responsible for autosomal dominant forms until late 2004, when the LRRK2 gene was identified (Paisan-Ruiz et al. , 2004; Zimprich et al. , 2004 a ). Despite their rarity, the discovery of α-synuclein mutations or multiplications led to the demonstration that α-synuclein is the major component of Lewy bodies, and clearly illustrated the gene dosage effect resulting from gene multiplications; duplications of the α-synuclein gene are responsible for a late-onset typical Parkinson's disease (Chartier-Harlin et al. , 2004; Ibanez et al. , 2004), whereas triplications result in an early-onset and rapidly progressive dementia with Lewy bodies (Singleton et al. , 2003), indicating the importance of the number of functional copies of this gene. It now turns out that LRRK2 is much more frequent and also has interesting features. The LRRK2 gene encodes a putative protein kinase named dardarin from dardara , the Basque term for tremor. From previous reports of LRRK2 families, it is known that the phenotype is mostly that of typical late-onset dopa-responsive Parkinson's disease, but with some intrafamilial variability (Funayama et al. , 2002; Nicholl et al. , 2002; Zimprich et al. , 2004 b ). The most striking variability concerns the neuropathological features. Although the dopaminergic neurons of the substantia nigra degenerate in all patients in association with gliosis, other pathological markers vary, even within the same family (Wszolek et al. , 2004). Several patients …