Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection
| Autor: | Emmanouela Leandrou, Nicolina Clemente, Adam Schaffner, Iban Ubarretxena-Belandia, Chen Yao, Zhenyu Yue, Xiaoluan Hua, Lianteng Zhi, Hui Zhang, Christopher J. H. Elliott, Nina Pan, Shu G. Chen, Xianting Li, Hardy J. Rideout, Anna Memou, Ming-Ming Zhou, Farinaz Afsari, Keita Morohashi, Yacob Gomez-Llorente, Chunyu Wang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0303 health sciences
Kinase Allosteric regulation HEK 293 cells Neurotoxicity Cell Biology Biology medicine.disease LRRK2 Neuroprotection nervous system diseases 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine Protein kinase domain medicine Kinase activity Molecular Biology 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Cell Research. 29:313-329 |
| ISSN: | 1748-7838 1001-0602 |
| DOI: | 10.1038/s41422-019-0153-8 |
| Popis: | Missense mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) cause the majority of familial and some sporadic forms of Parkinson's disease (PD). The hyperactivity of LRRK2 kinase induced by the pathogenic mutations underlies neurotoxicity, promoting the development of LRRK2 kinase inhibitors as therapeutics. Many potent and specific small-molecule LRRK2 inhibitors have been reported with promise. However, nearly all inhibitors are ATP competitive-some with unwanted side effects and unclear clinical outcome-alternative types of LRRK2 inhibitors are lacking. Herein we identify 5'-deoxyadenosylcobalamin (AdoCbl), a physiological form of the essential micronutrient vitamin B12 as a mixed-type allosteric inhibitor of LRRK2 kinase activity. Multiple assays show that AdoCbl directly binds LRRK2, leading to the alterations of protein conformation and ATP binding in LRRK2. STD-NMR analysis of a LRRK2 homologous kinase reveals the contact sites in AdoCbl that interface with the kinase domain. Furthermore, we provide evidence that AdoCbl modulates LRRK2 activity through disrupting LRRK2 dimerization. Treatment with AdoCbl inhibits LRRK2 kinase activity in cultured cells and brain tissue, and prevents neurotoxicity in cultured primary rodent neurons as well as in transgenic C. elegans and D. melanogaster expressing LRRK2 disease variants. Finally, AdoCbl alleviates deficits in dopamine release sustainability caused by LRRK2 disease variants in mouse models. Our study uncovers vitamin B12 as a novel class of LRRK2 kinase modulator with a distinct mechanism, which can be harnessed to develop new LRRK2-based PD therapeutics in the future. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink