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.
Pubmed ID: 34644545 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This monoclonal targets C-Myc
View all literature mentionsThis isotype control targets not applicable
View all literature mentionsThis polyclonal targets IgG (H+L)
View all literature mentionsThis isotype control targets Not Applicable
View all literature mentionsThis polyclonal targets Mouse IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets Mouse
View all literature mentionsThis monoclonal targets Mouse HA Peroxidase Clone 12CA5
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis monoclonal targets V5 Tag
View all literature mentionsThis monoclonal targets LAMP1
View all literature mentionsThis polyclonal targets Calreticulin
View all literature mentionsThis recombinant monoclonal targets LIMP2
View all literature mentionsThis monoclonal targets FLAG
View all literature mentionsThis monoclonal targets V5
View all literature mentionsThis monoclonal targets c-myc; Mouse monoclonal antibody (clone 9E10) IgG1 & 954;
View all literature mentionsThis monoclonal targets PINK1 (D8G3) Rabbit mAb
View all literature mentionsThis monoclonal targets Hsp75
View all literature mentionsThis monoclonal targets N-terminus of GRP 78 of human origin
View all literature mentionsThis monoclonal targets CANX
View all literature mentionsThis polyclonal targets SQSTM1 / p62
View all literature mentionsThis monoclonal targets Dopamine Transporter N-terminus clone DAT-Nt
View all literature mentionsThis monoclonal targets Ubiquitin, Lys63-Specific
View all literature mentionsThis monoclonal targets Ubiquitin, Lys48-Specific
View all literature mentionsThis monoclonal targets UBIQUITIN
View all literature mentionsThis unknown targets Tyrosine Hydroxylase
View all literature mentionsThis monoclonal targets Tyrosine Hydroxylase
View all literature mentionsThis monoclonal targets HNF-3beta (A-12)
View all literature mentionsThis unknown targets Nurr1
View all literature mentionsThis polyclonal targets Microtubule-Associated Protein 2 (MAP2)
View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis polyclonal targets GFAP
View all literature mentionsThis unknown targets Glucocerebrosidase, C Terminus
View all literature mentionsThis polyclonal targets GBA antibody
View all literature mentionsThis monoclonal targets GBA
View all literature mentionsThis monoclonal targets Actin, beta
View all literature mentionsThis monoclonal targets ATG5
View all literature mentionsThis monoclonal targets Alpha-synuclein filament
View all literature mentionsThis polyclonal targets SNCA
View all literature mentionsThis monoclonal targets Synuclein, alpha
View all literature mentionsThis monoclonal targets alpha Synuclein phosphorylated on Ser129
View all literature mentionsThis monoclonal targets alpha-Synuclein Phospho Ser129
View all literature mentionsMus musculus with name B6.Cg-2310039L15RikTg(Prnp-SNCA*A53T)23Mkle/J from IMSR.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
View all literature mentionsCell line SH-SY5Y is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions