. A cullin-RING ubiquitin ligase targets exogenous α-synuclein and inhibits Lewy body-like pathology. Sci Transl Med. 2019 Jun 5;11(495) PubMed.


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  1. This work by Gerez et al. helps us fill out the molecular machinery that controls uptake and degradation of α-synuclein from the extracellular space. Consistent with other literature, the authors seem to see a signature around endosomal pathways for uptake based on their differential proteome analysis. They then show convincingly that knockdown of the E3 ligase complex leads to greater accumulation of p-syn. There are some interesting aspects to this story that should be followed up. One important question is how material used to "seed" pathology and p-synuclein in the inclusions are related. Which material is the primary client of the E3 ligase is ambiguous based on available data and this might be resolved by identifying lysines for ubiquitin addition on seeds and endogenous synuclein. In principle, one could then determine whether the E3 ligase complex promotes degradation of the fibrils, the endogenous material, or both.

    It seems likely to me that there are going to be additional components of the endocytic machinery that are required for protein uptake into neurons in the brain. Many pathogens enter cells by "hijacking" the endocytosis pathways and it has been productive in other fields (e.g., virology) to use unbiased approaches such as the one used here to map out entry pathways. It would be important to continue searching for required molecular components for the transmission of α-synuclein and other protein assemblies.

    View all comments by Mark Cookson

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  1. Ubiquitin Ligase SCarFs Up Internalized α-Synuclein, Prevents Seeding