title: Nucleolar disruption in dopaminergic neurons leads to oxidative damage and parkinsonism through repression of mammalian target of rapamycin signaling.
abstract: The nucleolus represents an essential stress sensor for the cell. However, the molecular consequences of nucleolar damage and their possible link with neurodegenerative diseases remain to be elucidated. Here, we show that nucleolar damage is present in both genders in Parkinson's disease (PD) and in the pharmacological PD model induced by the neurotoxin 1,2,3,6-tetrahydro-1-methyl-4-phenylpyridine hydrochloride (MPTP). Mouse mutants with nucleolar disruption restricted to dopaminergic (DA) neurons show phenotypic alterations that resemble PD, such as progressive and differential loss of DA neurons and locomotor abnormalities. At the molecular level, nucleolar disruption results in increased p53 levels and downregulation of mammalian target of rapamycin (mTOR) activity, leading to mitochondrial dysfunction and increased oxidative stress, similar to PD. In turn, increased oxidative stress induced by MPTP causes mTOR and ribosomal RNA synthesis inhibition. Collectively, these observations suggest that the interplay between nucleolar dysfunction and increased oxidative stress, involving p53 and mTOR signaling, may constitute a destructive axis in experimental and sporadic PD.
authors.affiliation: Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Rieker
authors.forename: David
authors.initials: D
authors.lastname: Engblom
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Kreiner
authors.forename: Andrii
authors.initials: A
authors.lastname: Domanskyi
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
authors.forename: Stefanie
authors.initials: S
authors.lastname: Stotz
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Xuejun
authors.initials: X
authors.lastname: Yuan
authors.forename: Ingrid
authors.initials: I
authors.lastname: Grummt
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Rosanna
authors.initials: R
authors.lastname: Parlato
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002466:Cell Nucleolus / Q000378:metabolism / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology; D009048:Motor Skills; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D035463:Pol1 Transcription Initiation Complex Proteins; C491074:Rrn3 protein, mouse; D016159:Tumor Suppressor Protein p53; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D004298:Dopamine