Monitoring ?-synuclein ubiquitination dynamics reveals key endosomal effectors mediating its trafficking and degradation.

While defective ?-synuclein homeostasis is central to Parkinson's pathogenesis, fundamental questions about its degradation remain unresolved. We have developed a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of ?-synuclein and identified lysine residues 45, 58, and 60 as critical ubiquitination sites for its degradation. This ...
is mediated by NBR1 binding and entry into endosomes in a process that involves ESCRT I-III for subsequent lysosomal degradation. Autophagy or the autophagic chaperone Hsc70 is dispensable for this pathway. Antibodies against diglycine-modified ?-synuclein peptides confirmed that endogenous ?-synuclein is similarly ubiquitinated in the brain and targeted to lysosomes in primary and iPSC-derived neurons. Ubiquitinated ?-synuclein was detected in Lewy bodies and cellular models of aggregation, suggesting that it may be entrapped with endo/lysosomes in inclusions. Our data elucidate the intracellular trafficking of de novo ubiquitinated ?-synuclein and provide tools for investigating the rapidly turned-over fraction of this disease-causing protein.
Mesh Terms:
Endosomal Sorting Complexes Required for Transport, Endosomes, Lysosomes, Ubiquitin, Ubiquitination, alpha-Synuclein
Sci Adv
Date: Jun. 16, 2023
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