title: Genetic mutations linked to Parkinson's disease differentially control nucleolar activity in pre-symptomatic mouse models.
abstract: Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known asRRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation ofTIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.
authors.affiliation: Institute of Anatomy and Medical Cell Biology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Evsyukov
authors.affiliation: German Cancer Research Center, Molecular Biology of the Cell I, 69120 Heidelberg, Germany.|Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Andrii
authors.initials: A
authors.lastname: Domanskyi
authors.affiliation: German Cancer Research Center, Molecular Biology of the Cell II, 69120 Heidelberg, Germany.|Department of Biochemistry, Institute of Biochemistry and Biophysics, Center for Molecular Biomedicine (CMB), Friedrich Schiller University Jena, 07743 Jena, Germany.|Leibniz-Institute on Aging - Fritz Lipmann Institute (FLI), 07743 Jena, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Bierhoff
authors.affiliation: Experimental Neurology, Goethe University Medical School, 60590 Frankfurt am Main, Germany.
authors.forename: Suzana
authors.initials: S
authors.lastname: Gispert
authors.affiliation: Institute of Anatomy and Medical Cell Biology, University of Heidelberg, 69120 Heidelberg, Germany.|Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Rasem
authors.initials: R
authors.lastname: Mustafa
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Schlaudraff
authors.affiliation: Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Liss
authors.affiliation: Institute of Anatomy and Medical Cell Biology, University of Heidelberg, 69120 Heidelberg, Germany rosanna.parlato@uni-ulm.de.|Institute of Applied Physiology, University of Ulm, 89081 Ulm, Germany.
authors.forename: Rosanna
authors.identifier: 0000-0001-6682-9645
authors.initials: R
authors.lastname: Parlato
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000502:physiology*; D004275:DNA, Ribosomal / Q000235:genetics; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D000071617:Protein Deglycase DJ-1 / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D014158:Transcription, Genetic; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004275:DNA, Ribosomal; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase; C503466:PARK7 protein, mouse
keywords: Digenic model; Neuronal homeostasis; Nucleolus; Parkinson's disease; rRNA