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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.

SUBMITTER: Seo BA

PROVIDER: S-EPMC8639668 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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

Seo Bo Am BA Kim Donghoon D Hwang Heehong H Kim Min Seong MS Ma Shi-Xun SX Kwon Seung-Hwan SH Kweon Sin Ho SH Wang Hu H Yoo Je Min JM Choi Seulah S Kwon Sang Ho SH Kang Sung-Ung SU Kam Tae-In TI Kim Kwangsoo K Karuppagounder Senthilkumar S SS Kang Bong Gu BG Lee Saebom S Park Hyejin H Kim Sangjune S Yan Wei W Li Yong-Shi YS Kuo Sheng-Han SH Redding-Ochoa Javier J Pletnikova Olga O Troncoso Juan C JC Lee Gabsang G Mao Xiaobo X Dawson Valina L VL Dawson Ted M TM Ko Han Seok HS

Neuron 20211012 23

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 th ...[more]

PMID: 34644545

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Project description:Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.

Dataset Information

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

Publications

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

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