Burbulla LF, Jeon S, Zheng J, Song P, Silverman RB, Krainc D. A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease. Sci Transl Med. 2019 Oct 16;11(514) PubMed.
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National Institute on Aging
These two papers nicely complement each other in saying that lysosomal dysfunction and accumulation of α-synuclein are related, and are a potentially tractable therapy for PD. However, the two papers take different mechanistic approaches and therefore are worth comparing with each other. In some ways, the Burbulla et al. approach is more straightforward—if we know that loss of GCase activity is associated with PD, then increasing activity would be predicted to be therapeutically beneficial.
There are some theoretical uncertainties about this assumption, as there are, for example, variants in the encoding GBA gene that are not associated with Gaucher’s disease but increase risk of PD. However, this is less important in the context of the paper; so long as the compounds are helpful in models, the potential benefit for PD patients should be the important thing to focus on.
One thing that surprised me in the paper was the apparent benefit for idiopathic PD lines, as there is presumably little genetic risk to drive the oxidation of dopamine and accumulation of α-synuclein. It will be important to identify the mechanism by which these reprogrammed idiopathic lines retain these effects, so we can understand how and why GCase-directed molecules would benefit this larger group of patients.
The Cuddy et al. paper is a more complicated mechanism and a more complex pharmacological approach. The identification of ykt6 as a SNARE protein that interacts with α-synuclein to mediate lysosomal dysfunction is intriguing. Although there is exploration of ER-Golgi trafficking, which is logical given the prior literature in this area, it would have been interesting to also examine ykt6 at the autophagosome, where it is also implicated as being important.
The targeting of ykt6 via farnesylation is, however, a little bit more complicated than the simple approach used by Burbulla et al. Farnesyl transferases should prevent addition of lipid moiety to multiple cellular signaling proteins. Therefore, the compound used certainly affects ykt6 but also likely some other proteins, potentially adding to its effects on cells. Whether this would be helpful to human PD remains to be established, although it is potentially of interest that farnesyltransferase inhibitors have been assessed clinically in premature aging syndromes.
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