ArticleNeuron2021
TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.
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Article in Neuron, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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35citing papers in PubMed
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Who cites it
35 citing papers in PubMed, 51 citations in OpenAlex.
- Interplay of GBA1 with lysosomal dysfunction and inflammation in Parkinson's disease.Neural regeneration research · 2026Article
- TRIP12 promotes HIV-1 replication and latency reactivation by stabilizing Tat via USP7-mediated deubiquitination.Journal of virology · 2026Article
- Polymeric nanoparticle-mediated GBA1 gene therapy is neuroprotective in a preclinical model of Parkinson's disease.Drug delivery and translational research · 2026Article
- Cell type transcriptomic modules reveal shared molecular mechanisms in Alzheimer's and Parkinson's disease.GigaScience · 2026Article
- MIRAGE: A Bayesian statistical method for gene-level rare-variant analysis incorporating functional annotations.American journal of human genetics · 2026Article
- E3 ubiquitin ligases in neurodegenerative diseases.Military Medical Research · 2026Review
- Unraveling the impact ofBrain communications · 2026Article
- Ubiquitination of TFEB increased intestinal permeability to aggravate metabolic dysfunction-associated steatohepatitis.Hepatology (Baltimore, Md.) · 2025Article
- Ubiquitination in the Nervous System: From Molecular Mechanisms to Disease Implications.Molecular neurobiology · 2025Review
- The Role of Ubiquitination and Deubiquitination in the Pathogenesis of Acute Kidney Injury: Progress in Research.Biomedicines · 2025Review
- Dynamic regulation of the oxidative stress response by the E3 ligase TRIP12.Cell reports · 2025Article
- TRIP12 structures reveal HECT E3 formation of K29 linkages and branched ubiquitin chains.Nature structural & molecular biology · 2025Article
- Exogenous α-Synuclein Induces Oxidative Damage to Dopaminergic Neurons Through p-NMDAR2B/Nur77.Molecular neurobiology · 2025Article
- Nanozymes: Innovative Therapeutics in the Battle Against Neurodegenerative Diseases.International journal of molecular sciences · 2025Review
- Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.Molecular neurodegeneration · 2025Review
- Gba1 E326K renders motor and non-motor symptoms with pathological α-synuclein, tau and glial activation.Brain : a journal of neurology · 2024Article
- Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.Nature communications · 2024Article
- Preserving cognitive function in patients with Alzheimer's disease: The Alzheimer's disease neuroprotection research initiative (ADNRI).Neuroprotection (Chichester, England) · 2023Article
- EZH2 K63-polyubiquitination affecting migration in extranodal natural killer/T-cell lymphoma.Clinical epigenetics · 2023Article
- Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12.Cell death & disease · 2023Article
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Authors and funding
30 authors at 4 institutions in 3 countries.
Bo Am SeoNeuroregeneration 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.
Donghoon KimNeuroregeneration 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.
Heehong HwangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Min Seong KimNeuroregeneration 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.
Shi-Xun MaNeuroregeneration 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.
Seung-Hwan KwonNeuroregeneration 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.
Sin Ho KweonNeuroregeneration 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.
Hu WangNeuroregeneration 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.
Je Min YooDepartment 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.
Seulah ChoiNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sang Ho KwonNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sung-Ung KangNeuroregeneration 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.
Tae-In KamNeuroregeneration 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.
Kwangsoo KimVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA.
Senthilkumar S KaruppagounderNeuroregeneration 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.
Bong Gu KangNeuroregeneration 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.
Saebom LeeNeuroregeneration 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.
Hyejin ParkNeuroregeneration 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.
Sangjune KimNeuroregeneration 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.
Wei YanNeuroregeneration 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.
Yong-Shi LiDepartment of Neurology, Columbia University, New York, NY, USA.
Sheng-Han KuoDepartment of Neurology, Columbia University, New York, NY, USA.
Javier Redding-OchoaDepartment of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Olga PletnikovaDepartment of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Juan C TroncosoDepartment 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.
Gabsang LeeNeuroregeneration 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.
Xiaobo MaoNeuroregeneration 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.
Valina L DawsonNeuroregeneration 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.
Ted M DawsonNeuroregeneration 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.
Han Seok KoNeuroregeneration 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.
Johns Hopkins University · USColumbia University · USBaylor College of Medicine · USNational University College · PR
Funding
Understanding Mechanisms of a-synuclein pathologyP50NS038377 · NINDS · JOHNS HOPKINS UNIVERSITY · PI KO, HANSEOK · 1998 to 2019
$38.8MThe role of NOD2/RIPK2 signaling in the pathogenesis of Parkinson's DiseaseR01NS107404 · NINDS · JOHNS HOPKINS UNIVERSITY · PI KO, HANSEOK · 2018 to 2022
$1.8MGlucocerebrosidase Biology and It's Role in Parkinson's DiseaseR01NS082205 · NINDS · JOHNS HOPKINS UNIVERSITY · PI KO, HANSEOK · 2013 to 2017
$1.8MCharacterization and Validation of Mouse VPS35 Model of Parkinson's DiseaseR21NS098006 · NINDS · JOHNS HOPKINS UNIVERSITY · PI KO, HANSEOK · 2017 to 2018
$449kNINDS NIH HHS P50 NS038377NINDS NIH HHS R01 NS082205NINDS NIH HHS R01 NS107404NINDS NIH HHS R21 NS098006
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.
Indexed as
GlucosylceramidaseParkinson Diseasealpha-SynucleinAnimalsBrainCarrier ProteinsDisease Models, AnimalMiceUbiquitinationUbiquitin-Protein Ligasesalpha-SynucleinCarrier ProteinsGlucosylceramidaseTRIP12 protein, humanUbiquitin-Protein LigasesGaucher’s disease (GD)glucocerebrosidase 1 gene (GBA1)glucocerebrosidase (GCase)glucosylceramide (GlcCer)lysosomemitochondriaParkinson’s disease (PD)Thyroid Hormone Receptor Interacting Protein 12 (TRIP12)α-synucleinα-synuclein preformed fibrils (α-syn PFFs)
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