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 Yan; Yong-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

doi:10.1016/j.neuron.2021.09.031

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

Neuron. 2021 Dec 1;109(23):3758-3774.e11. doi: 10.1016/j.neuron.2021.09.031. Epub 2021 Oct 12.

Authors

Bo Am Seo¹, Donghoon Kim², Heehong Hwang³, Min Seong Kim¹, Shi-Xun Ma¹, Seung-Hwan Kwon¹, Sin Ho Kweon¹, Hu Wang¹, Je Min Yoo⁴, Seulah Choi³, Sang Ho Kwon³, Sung-Ung Kang⁵, Tae-In Kam⁶, Kwangsoo Kim⁷, Senthilkumar S Karuppagounder¹, Bong Gu Kang¹, Saebom Lee¹, Hyejin Park⁵, Sangjune Kim⁸, Wei Yan¹, Yong-Shi Li⁹, Sheng-Han Kuo⁹, Javier Redding-Ochoa¹⁰, Olga Pletnikova¹⁰, Juan C Troncoso¹¹, Gabsang Lee¹², Xiaobo Mao¹, Valina L Dawson¹³, Ted M Dawson¹⁴, Han Seok Ko¹⁵

Affiliations

¹ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology, Peripheral Neuropathy Research Center (PNRC), Dong-A University College of Medicine, Busan, Republic of Korea. Electronic address: dkim@dau.ac.kr.
³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁴ Department of Chemistry, Krieger School of Arts and Sciences, Johns Hopkins University, Baltimore, MD, USA; Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea.
⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA.
⁶ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
⁷ Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
⁸ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Biology, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.
⁹ Department of Neurology, Columbia University, New York, NY, USA.
¹⁰ Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹² Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹³ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA.
¹⁴ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. Electronic address: tdawson@jhmi.edu.
¹⁵ Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA; Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, USA; Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA. Electronic address: hko3@jhmi.edu.

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.

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).

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain / metabolism
Carrier Proteins / metabolism*
Disease Models, Animal
Glucosylceramidase* / genetics
Glucosylceramidase* / metabolism
Mice
Parkinson Disease* / genetics
Parkinson Disease* / metabolism
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination
alpha-Synuclein / metabolism

Substances

Carrier Proteins
alpha-Synuclein
TRIP12 protein, human
Ubiquitin-Protein Ligases
Glucosylceramidase

Abstract

Publication types

MeSH terms

Substances

Grants and funding