Ángel Raya, who heads IBEC’s Control of Stem Cell Potency group, and his collaborators in Italy and the USA have been looking at an important gene, dardarin, mutations of which have been found to be the most common cause of familial Parkinson’s. The normal function of dardarin – which gets its name from the Basque word “dardara”, or trembling – or how mutations lead to the disease, however, have long been elusive.
In the paper published today in Nature Neuroscience, the researchers reveal their discovery that dardarin is broken down by a cleaning-up process called autophagy, which enables the recycling of amino acids of degraded proteins and eliminates abnormal or damaged ones. But dardarin uses a very specific type of autophagy and does it in a rather peculiar way, so that its mutations are also able to strike out at autophagy itself and undermine its efficiency.
As if that’s not bad enough, this has an effect on another crucial process that can lead to Parkinson’s: the build-up of a protein called α-synuclein. Usually, α-synuclein – or α-syn – is also degraded by autophagy; but when autophagy is compromised by dardarin, α-syn is able to accumulate.
This ‘double-whammy’ attack inhibiting autophagy could underlie toxicity in Parkinson’s disease. “In other words, two dominant features that cause Parkinson’s disease converge at the same step,” explains Ángel.
This new discovery – which has been made possible by the use of induced pluripotent stem cells from patients, already proving that it is applicable to humans – may help uncover specific strategies for dealing with or even preventing the neurodegenerative motor disorder. “As a result, interventions aimed at enhancing autophagy activity or at preventing its decrease in pathologies and with age may prove to be valuable,” says Ángel. “This applies not just to the treatment of Parkinson’s disease, but may also be relevant for other age-related disorders resulting from alterations in cellular self-regulation.”
S J Orenstein, S Kuo, I Tasset, E Arias, H Koga, I Fernandez-Carasa, E Cortes, L S Honig, W Dauer, A Consiglio, A Raya, D Sulzer & A M Cuervo (2013). “Interplay of LRRK2 with chaperone-mediated autophagy“, Nat Neuroscience.