Summary: Vitamin B12 significantly prevents the neurotoxicity of LRRK2 genetic variants associated with hereditary Parkinson’s disease. The findings may help with the development of new therapies to combat the neurodegenerative disease.
Source: University of the Basque Country
Parkinson’s is the most common, chronic neurodegenerative movement disorder affecting 1% of the global population over seventy years of age. Right now, there is no cure for this disease and the available treatments focus on addressing its symptoms but not its progression.
Although most cases of Parkinson’s are sporadic, the inheritable variants of the disease are mainly associated with mutations of the gene that encodes the LRRK2 enzyme. In 2004 an international research team, in which researchers from the Basque Country participated, established the link between one of the mutations in this enzyme and patients diagnosed with the disease.
So the LRRK2 enzyme, which is also known internationally by the name “dardarina”, the Basque word that means tremor, has become one of the most attractive therapeutic targets for developing new drugs to combat inheritable Parkinson’s. Neurotoxicity, or the pathogenic effects as a whole associated with LRRK2, is mainly due to the fact that pathogenic mutations increase the kinase activity of this enzyme, which has prompted an international race to develop inhibitors. Right now, specific, powerful inhibitors of the kinase activity of LRRK2 do in fact exist. Yet many of them cause undesirable side effects or produce very unclear clinical results.
This research conducted by Iban Ubarretxena, the Ikerbasque researcher and director of the Biofisika Institute (mixed centre of the CSIC-Spanish National Research Council and the UPV/EHU-University of the Basque Country) at the UPV/EHU’s Science Park (Leioa-Erandio Area), together with an international research team, has revealed that AdoCbl, one of the active forms of vitamin B12, acts as an inhibitor of the kinase activity of LRRK2 in cultured cells and brain tissue. It also significantly prevents the neurotoxicity of the LRRK2 variants associated with Parkinson’s in cultured cells of primary rodents, as well as in various genetically modified models used to study this disease. The results of the research have been published in the prestigious journal Cell Research.
So according to the study, vitamin B12 has turned out to be a new class of modulator of the kinase activity of LRRK2, which, as Iban Ubarretxena pointed out, “constitutes a huge step forward because it is a neuroprotective vitamin in animal models and has a mechanism unlike that of currently existing inhibitors. So it could be used as a basis to develop new therapies to combat hereditary Parkinson’s associated with pathogenic variants of the LRRK2 enzyme”.
Vitamin B12 modulates Parkinson’s disease LRRK2 kinase activity through allosteric regulation and confers neuroprotection
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.