LRRK2 interactions with α-synuclein in Parkinson’s disease brains and in cell models
| Autor: | Wei Ping Gai, Yue Huang, Amanda M. Gysbers, Tiago F. Outeiro, Danni Cheng, Glenda M. Halliday, Patrícia Guerreiro |
|---|---|
| Jazyk: | angličtina |
| Předmět: |
Pathology
Parkinson's disease Gene Expression chemistry.chemical_compound Mice 0302 clinical medicine Drug Discovery Genetics(clinical) Biomedicine Molecular Medicine Human Genetics Internal Medicine Genetics (clinical) α-Synuclein Mice Knockout Medicine(all) 0303 health sciences Kinase LRKK2 Parkinson’s disease Lewy bodies Interaction Brain Parkinson Disease LRRK2 Cell biology medicine.anatomical_structure Gene Knockdown Techniques alpha-Synuclein Original Article Protein Binding medicine.medical_specialty Biology Protein Serine-Threonine Kinases Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Cell Line 03 medical and health sciences medicine Animals Humans Anterior cingulate cortex 030304 developmental biology Alpha-synuclein Lewy body medicine.disease Molecular medicine nervous system diseases Disease Models Animal chemistry nervous system Cell culture 030217 neurology & neurosurgery |
| Zdroj: | Journal of Molecular Medicine Journal of Molecular Medicine (Berlin, Germany) |
| ISSN: | 0946-2716 |
| DOI: | 10.1007/s00109-012-0984-y |
| Popis: | Mutations in the genes encoding leucine-rich repeat kinase 2 (LRRK2) and α-synuclein are associated with both autosomal dominant and idiopathic forms of Parkinson’s disease (PD). α-Synuclein is the main protein in Lewy bodies, hallmark inclusions present in both sporadic and familial PD. We show that in PD brain tissue, the levels of LRRK2 are positively related to the increase in α-synuclein phosphorylation and aggregation in affected brain regions (amygdala and anterior cingulate cortex), but not in the unaffected visual cortex. In disease-affected regions, we show co-localization of these two proteins in neurons and Lewy body inclusions. Further, in vitro experiments show a molecular interaction between α-synuclein and LRRK2 under endogenous and over-expression conditions. In a cell culture model of α-synuclein inclusion formation, LRRK2 co-localizes with the α-synuclein inclusions, and knocking down LRRK2 increases the number of smaller inclusions. In addition to providing strong evidence for an interaction between LRRK2 and α-synuclein, our results shed light on the complex relationship between these two proteins in the brains of patients with PD and the underlying molecular mechanisms of the disease. Electronic supplementary material The online version of this article (doi:10.1007/s00109-012-0984-y) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|