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Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, α‐synuclein, and tau
Author(s) -
Taymans JeanMarc,
Cookson Mark R.
Publication year - 2010
Publication title -
bioessays
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.175
H-Index - 184
eISSN - 1521-1878
pISSN - 0265-9247
DOI - 10.1002/bies.200900163
Subject(s) - lrrk2 , parkinsonism , parkinson's disease , pathogenesis , biology , gene , genetics , lewy body , gtpase , kinase , chromosomal translocation , disease , microbiology and biotechnology , mutation , medicine , pathology , immunology
Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, α‐synuclein ( SNCA ) and leucine‐rich repeat kinase 2 ( LRRK2 ), are important for understanding inherited and sporadic PD. SNCA is a major component of pathologic inclusions termed Lewy bodies found in PD. LRRK2 is found in a significant proportion of PD cases. These two proteins may be linked as most LRRK2 PD cases have SNCA ‐positive Lewy bodies. Mutations in both proteins are associated with toxic effects in model systems although mechanisms are unclear. LRRK2 is an intracellular signaling protein possessing both GTPase and kinase activities that may contribute to pathogenicity. A third protein, tau, is implicated as a risk factor for PD. We discuss the potential relationship between these genes and suggest a model for PD pathogenesis where LRRK2 is upstream of pathogenic effects through SNCA , tau, or both proteins.