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

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

School of Medicine

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	3758-3774.e11
Journal	Neuron
Volume	109
Issue number	23
DOIs	https://doi.org/10.1016/j.neuron.2021.09.031
State	Published - Dec 1 2021

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

General Neuroscience

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10.1016/j.neuron.2021.09.031

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Seo, B. A., Kim, D., Hwang, H., Kim, M. S., Ma, S. X., Kwon, S. H., Kweon, S. H., Wang, H., Yoo, J. M., Choi, S., Kwon, S. H., Kang, S. U., Kam, T. I., Kim, K., Karuppagounder, S. S., Kang, B. G., Lee, S., Park, H., Kim, S., ... Ko, H. S. (2021). TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease. Neuron, 109(23), 3758-3774.e11. https://doi.org/10.1016/j.neuron.2021.09.031

Seo, BA, Kim, D, Hwang, H, Kim, MS, Ma, SX, Kwon, SH, Kweon, SH, Wang, H, Yoo, JM, Choi, S, Kwon, SH, Kang, SU, Kam, TI, Kim, K, Karuppagounder, SS, Kang, BG, Lee, S, Park, H, Kim, S, Yan, W, Li, YS, Kuo, SH, Redding-Ochoa, J, Pletnikova, O, Troncoso, JC , Lee, G , Mao, X , Dawson, VL , Dawson, TM & Ko, HS 2021, 'TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease', Neuron, vol. 109, no. 23, pp. 3758-3774.e11. https://doi.org/10.1016/j.neuron.2021.09.031

@article{21b6e5c307c14c51a9f1c7310e3eb9c1,

title = "TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease",

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)",

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

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = dec,

day = "1",

doi = "10.1016/j.neuron.2021.09.031",

language = "English (US)",

volume = "109",

pages = "3758--3774.e11",

journal = "Neuron",

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TY - JOUR

T1 - TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease

AU - Seo, Bo Am

AU - Kim, Donghoon

AU - Hwang, Heehong

AU - Kim, Min Seong

AU - Ma, Shi Xun

AU - Kwon, Seung Hwan

AU - Kweon, Sin Ho

AU - Wang, Hu

AU - Yoo, Je Min

AU - Choi, Seulah

AU - Kwon, Sang Ho

AU - Kang, Sung Ung

AU - Kam, Tae In

AU - Kim, Kwangsoo

AU - Karuppagounder, Senthilkumar S.

AU - Kang, Bong Gu

AU - Lee, Saebom

AU - Park, Hyejin

AU - Kim, Sangjune

AU - Yan, Wei

AU - Li, Yong Shi

AU - Kuo, Sheng Han

AU - Redding-Ochoa, Javier

AU - Pletnikova, Olga

AU - Troncoso, Juan C.

AU - Lee, Gabsang

AU - Mao, Xiaobo

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Ko, Han Seok

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

KW - Gaucher's disease (GD)

KW - Parkinson's disease (PD)

KW - Thyroid Hormone Receptor Interacting Protein 12 (TRIP12)

KW - glucocerebrosidase (GCase)

KW - glucocerebrosidase 1 gene (GBA1)

KW - glucosylceramide (GlcCer)

KW - lysosome

KW - mitochondria

KW - α-synuclein

KW - α-synuclein preformed fibrils (α-syn PFFs)

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U2 - 10.1016/j.neuron.2021.09.031

DO - 10.1016/j.neuron.2021.09.031

M3 - Article

C2 - 34644545

AN - SCOPUS:85119936531

SN - 0896-6273

VL - 109

SP - 3758-3774.e11

JO - Neuron

JF - Neuron

IS - 23

ER -

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

Abstract

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