title: Repression of rRNA transcription by PARIS contributes to Parkinson's disease.
abstract: The nucleolus is a compartment for the transcription of ribosomal RNA (rRNA) and assembly of ribosome subunits. Dysregulation of the nucleolus is considered to be a cellular stress event associated with aging and neurodegenerative disease, including Parkinson's disease (PD). We previously demonstrated that PARIS (PARkin Interacting Substrate, ZNF746) transcriptionally suppresses peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC-1α) in PD and its accumulation results in selective dopaminergic neuronal death. However, functional knowledge of PARIS is limited, and no other studies have been performed to elucidate its function. Here, we used tandem-affinity purification to identify the binding partners of PARIS, showing that PARIS interacts with 160-kDa Myb-binding protein 1α (MYBBP1A), which suppresses rRNA transcription and the rRNA editing process. Interestingly, PARIS was also found to interact with the components of RNA polymerase I, occupied the promoter of rDNA, and suppressed rDNA transcription in vivo. Accordingly, we observed a reduction of rRNA levels and increased expression of p53, a molecular marker of nucleolar stress, in the substantia nigra of conditional parkin knockout mice, AAV-mediated PARIS overexpression mice, and in patients with sporadic PD. Together, our results suggest that dysfunction of the Parkin-PARIS pathway may play a deleterious role in rRNA transcription and contribute to PD pathogenesis.
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, Republic of Korea.
authors.forename: Hojin
authors.initials: H
authors.lastname: Kang
authors.affiliation: Division of Pharmacology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, Republic of Korea; Mass Spectrometry, Research Core Facility, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi-do 440-746, Republic of Korea. Electronic address: jshin24@skku.edu.
authors.forename: Joo-Ho
authors.initials: JH
authors.lastname: Shin
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013378:Substantia Nigra / Q000378:metabolism*; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C110421:Mybbp1a protein, mouse; D009687:Nuclear Proteins; D012335:RNA, Ribosomal; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C000591313:ZNF746 protein, human; C557561:ZNF746 protein, mouse; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: MYBBP1A; PARIS; Parkinson's disease; rRNA biogenesis