Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, alpha-synuclein, and tau.
Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, alpha-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.
Taymans
Jean-Marc
JM
Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, MD, USA.|Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium.
Cookson
Mark R
MR
Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, NIA, National Institutes of Health, Bethesda, MD, USA.
D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D015398:Signal Transduction / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity
D051844:alpha-Synuclein; D016875:tau Proteins; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases