These finding means that this form of vitamin B12 could be used as the basis for developing new therapies for treating Parkinson’s.
Several studies have shown that overactivation of the LRRK2 enzyme, due to genetic mutations in the LRRK2 gene, is associated with the development of a hereditary form of Parkinson’s disease. But increasing evidence has suggested that this enzyme also may contribute to the progression of sporadic cases of Parkinson’s — ones caused by environmental factors.
Increased activity of the LRRK2 enzyme contributes to the accumulation of toxic alpha-synuclein fibers in dopamine-producing neurons of the substantia nigra — a brain region involved in the control of voluntary movements, and one of the most affected in Parkinson’s disease.
Given its important role, researchers have focused on finding ways to prevent the activity of this enzyme as a strategy for treating this neurodegenerative disorder.
Now, an international team of researchers has found that one natural variant of vitamin B12, called AdoCbl (5’-deoxyadenosylcobalamin), can effectively regulate the activity of the LRRK2 enzyme. AdoCbl is approved by the U.S. Food and Drug Administration.
When tested in experimental cell line models, the team found that AdoCbl could significantly reduce the enzyme’s activity, even when it was genetically modified to carry the G2019S mutation — the most common LRRK2 variant linked to Parkinson’s.
Further analysis confirmed that AdoCbl had the ability to directly bind to LRRK2, changing its three-dimensional structure, and preventing its normal function. This allows AdoCbl to work as a strong inhibitor of the enzyme.
“AdoCbl represents a starting point for the development of a new class of LRRK2 activity modulators for the much-needed treatment of LRRK2-linked pathological conditions such as Parkinson’s disease,” the researchers said.
To explore AdoCbl’s therapeutic potential, the team next administrated it in worms carrying the G2019S mutation. The experiments revealed that AdoCbl treatment could prevent the death of dopamine-producing nerve cells and prevent the manifestation of symptoms associated with neurodegeneration.
Additional analysis also revealed that AdoCbl could prevent neurotoxicity and dopamine deficits in fly and mouse models carrying different LRRK2 mutations associated with Parkinson’s.
Identification of vitamin B12 as a modulator of LRRK2 activity “constitutes a huge step forward because it is a neuroprotective vitamin in animal models and has a mechanism unlike that of currently existing inhibitors,” Iban Ubarretxena, director of the Biofisika Institute and co-author of the study, said in a press release. Biofisika is a joint research center of the University of the Basque Country (Universidad del País Vasco/Euskal Herriko Unibertsitatea).
“[This active form of vitamin B12] could be used as a basis to develop new therapies to combat hereditary Parkinson’s associated with pathogenic variants of the LRRK2 enzyme,” he added.