. Stress-Induced Cellular Clearance Is Mediated by the SNARE Protein ykt6 and Disrupted by α-Synuclein. Neuron. 2019 Oct 9; PubMed.

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  1. 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.

    View all comments by Mark Cookson
  2. Increasingly, the lysosome is becoming the centerpiece for understanding the cell biology of inclusion body neurodegenerative diseases. The fascinating paper by Cuddy et al. adds an intricate layer of regulation over lysosomal activation in the context of the synucleinopathies.

    The study is now the second report to implicate farnesyl transferase inhibition in the activation of the lysosome and consequently amelioration of pathology—in one case, the inhibition of farnesylation prevented tau pathology (Hernandez et al., 2019), and now a mouse model that expresses human A53T α-syn within dopaminergic neurons (DASYN53) was rescued by intraperitoneal injection of a farnesyl-transferase inhibitor (FTI).

    The starting point for the study was the observation that lysosomal dysfunction in the context of induced pluripotent stem cell-derived neurons harboring the A53T α-syn mutation results from disrupted protein maturation (Cooper et al., 2006). The impaired maturation pointed to ER-Golgi traffic, and additional experiments pinpointed a mediator of this traffic, ykt6, which co-IP’ed with α-syn.

    The α-syn-ykt6 complexes occurred in the cytosol, and this complex inhibited ykt6 membrane association. The intellectual jump to a therapeutic was the observation that farnesylation-incompetent ykt6 augmented lysosomal activity compared to the wild-type, which prompted experiments using the selective FTI LNK-754. Treatment with the FTI increased ykt6’s membrane association, and lysosomal activity.

    The counterintuitive effect of an FTI on ykt6 has been explained previously (Wen et al., 2010): The farnesyl group keeps the protein in its water-soluble conformation by sequestering the lipid group inside a hydrophobic pocket. Palmitoylation of ykt6 increases the partition coefficient of the double-lipidated protein to membranes, thereby shifting some pools of the protein from the cytosol to cellular membranes. These data support scrutiny of all the complex regulatory components involved in double-lipidated proteins and their attachment to specific membrane compartments as an entrée for the development of novel pharmaceuticals.

    FTIs have now been implicated as a potential therapeutic option for two neurodegenerative inclusions. That said, it is important to point out the difficulty of pinpointing the precisely relevant farnesylation substrates, because this post-translational modification is so widely used. The relevant substrate for an FTI proposed for tau clearance was Rhes, and in this case, it is ykt6. In the former case, an FTI will result in loss of membrane association; in the case of ykt6, an FTI will increase membrane association. Among the bases for this difference is probably the contrasting ability of these proteins to be palmitoylated.

    Another contrast is the possibly different physico-chemical states of the pathological entities recognized by these two pathways. Rhes can sense the presence of aberrant tau well before aggregates are present, whereas ykt6 appears to sense α-syn after the mutant form begins to harden. This difference points to the importance of identifying the phase state of a disordered protein that activates proteostasis.

    References:

    . A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med. 2019 Mar 27;11(485) PubMed.

    . Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models. Science. 2006 Jul 21;313(5785):324-8. PubMed.

    . Lipid-Induced conformational switch controls fusion activity of longin domain SNARE Ykt6. Mol Cell. 2010 Feb 12;37(3):383-95. PubMed.

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