Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease

Zoi Alexopoulou, Johannes Lang, Rebecca M Perrett, Myriam Elschami, Madeleine E D Hurry, Hyoung Tae Kim, Dimitra Mazaraki, Aron Szabo, Benedikt M Kessler, Alfred Lewis Goldberg, Olaf Ansorge, Tudor A Fulga, George K Tofaris

Research output: Contribution to journalArticlepeer-review


In Parkinson's disease, misfolded α-synuclein accumulates, often in a ubiquitinated form, in neuronal inclusions termed Lewy bodies. An important outstanding question is whether ubiquitination in Lewy bodies is directly relevant to α-synuclein trafficking or turnover and Parkinson's pathogenesis. By comparative analysis in human postmortem brains, we found that ubiquitin immunoreactivity in Lewy bodies is largely due to K63-linked ubiquitin chains and markedly reduced in the substantia nigra compared with the neocortex. The ubiquitin staining in cells with Lewy bodies inversely correlated with the content and pathological localization of the deubiquitinase Usp8. Usp8 interacted and partly colocalized with α-synuclein in endosomal membranes and, both in cells and after purification, it deubiquitinated K63-linked chains on α-synuclein. Knockdown of Usp8 in the Drosophila eye reduced α-synuclein levels and α-synuclein-induced eye toxicity. Accordingly, in human cells, Usp8 knockdown increased the lysosomal degradation of α-synuclein. In the dopaminergic neurons of the Drosophila model, unlike knockdown of other deubiquitinases, Usp8 protected from α-synuclein-induced locomotor deficits and cell loss. These findings strongly suggest that removal of K63-linked ubiquitin chains on α-synuclein by Usp8 is a critical mechanism that reduces its lysosomal degradation in dopaminergic neurons and may contribute to α-synuclein accumulation in Lewy body disease.

Original languageEnglish
Pages (from-to)E4688-97
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number32
Publication statusPublished - 9 Aug 2016
Externally publishedYes


  • Animals
  • Dopaminergic Neurons/metabolism
  • Drosophila
  • Endopeptidases/physiology
  • Endosomal Sorting Complexes Required for Transport/physiology
  • Humans
  • Lewy Bodies/metabolism
  • Lewy Body Disease/metabolism
  • Lysosomes/metabolism
  • Male
  • Ubiquitin/analysis
  • Ubiquitin Thiolesterase/physiology
  • Ubiquitination
  • alpha-Synuclein/analysis


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