TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease

Bo Am Seo, Donghoon Kim, Heehong Hwang, Min Seong Kim, Shi Xun Ma, Seung Hwan Kwon, Sin Ho Kweon, Hu Wang, Je Min Yoo, Seulah Choi, Sang Ho Kwon, Sung Ung Kang, Tae In Kam, Kwangsoo Kim, Senthilkumar S. Karuppagounder, Bong Gu Kang, Saebom Lee, Hyejin Park, Sangjune Kim, Wei YanYong Shi Li, Sheng Han Kuo, Javier Redding-Ochoa, Olga Pletnikova, Juan C. Troncoso, Gabsang Lee, Xiaobo Mao, Valina L. Dawson, Ted M. Dawson, Han Seok Ko

Research output: Contribution to journalArticlepeer-review

Abstract

Impairment in glucocerebrosidase (GCase) is strongly associated with the development of Parkinson's disease (PD), yet the regulators responsible for its impairment remain elusive. In this paper, we identify the E3 ligase Thyroid Hormone Receptor Interacting Protein 12 (TRIP12) as a key regulator of GCase. TRIP12 interacts with and ubiquitinates GCase at lysine 293 to control its degradation via ubiquitin proteasomal degradation. Ubiquitinated GCase by TRIP12 leads to its functional impairment through premature degradation and subsequent accumulation of α-synuclein. TRIP12 overexpression causes mitochondrial dysfunction, which is ameliorated by GCase overexpression. Further, conditional TRIP12 knockout in vitro and knockdown in vivo promotes the expression of GCase, which blocks α-synuclein preformed fibrils (α-syn PFFs)-provoked dopaminergic neurodegeneration. Moreover, TRIP12 accumulates in human PD brain and α-synuclein-based mouse models. The identification of TRIP12 as a regulator of GCase provides a new perspective on the molecular mechanisms underlying dysfunctional GCase-driven neurodegeneration in PD.

Original languageEnglish (US)
Pages (from-to)3758-3774.e11
JournalNeuron
Volume109
Issue number23
DOIs
StatePublished - Dec 1 2021
Externally publishedYes

Keywords

  • Gaucher's disease (GD)
  • Parkinson's disease (PD)
  • Thyroid Hormone Receptor Interacting Protein 12 (TRIP12)
  • glucocerebrosidase (GCase)
  • glucocerebrosidase 1 gene (GBA1)
  • glucosylceramide (GlcCer)
  • lysosome
  • mitochondria
  • α-synuclein
  • α-synuclein preformed fibrils (α-syn PFFs)

ASJC Scopus subject areas

  • Neuroscience(all)

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