Die Wirkung von Ataxin-2-Defizienz bzw. -Überexpression auf mRNA-3'-Prozessierung und stress granules in Hefe, Maus und Mensch

• Antragstellerinnen / Antragsteller: Professor Dr. Georg Auburger; Dr. Sylvia Krobitsch
• Fachliche Zuordnung: Molekulare und zelluläre Neurologie und Neuropathologie
• Förderung: Förderung von 2010 bis 2015
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 186801903

• Erstellungsjahr: 2015

Zusammenfassung der Projektergebnisse

Aim 1: The project showed conclusively that Ataxin-2 (ATXN2) knockout (KO) in mouse selectively controls specific mitochondrial precursors regarding their mRNA levels (e.g. the transcript "IVD", "PINK1") and their translation (e.g. the proteins IVD, PCCA, ACADS, OTC, ALDH6A1, MCCC2), as well as pyruvate metabolism pathways, in periods of cell stress and mitochondrial dysfunction. Similarly in yeast, its orthologue PBP1 controls specific mitochondrial precursors (in charge of amino acid and citric acid cycle) as well as glucose metabolism, in stress periods via GIS2 as a stress granule component, effects that are clearly reproduced in human neuroblastoma cells. In SCA2 patients, analogous changes are detectable even in blood, and overall an inhibition of growth signals via the mTOR pathway ensues. The global effect of Ataxin-2 deletion is a decrease in translation rates, which triggers an upregulation of translation machinery. Our observations were confirmed by independent teams in C. elegans worms and in yeast. Aim 2: Understanding the neuroprotective effects of Ataxin-2-KO: The neuroprotective effect of Atxn2-KO for TDP-43-neurotoxicity has been demonstrated in double mouse mutants in a manuscript that is currently positively reviewed. The ATXN2-ATXN1 double mouse mutant analysis was not a successful project part. Analogous experiments in yeast remain to be published. Aim 3: Mouse models of SCA2 via knock-in of expansions CAG42, and CAG100 have demonstrated that downregulated calcium homeostasis factors are an important part of pathogenesis, while the upregulated FBXW8 protein degradation enzyme is an important compensatory event. In cooperation with the Max Planck Institute for Molecular Genetics in Berlin, our Frankfurt team has obtained the global proteome profile of these mice, which confirmed a key role of the downregulated mitochondrial precursor proteins. In conclusion, the project results have 1) elucidated the mechanism of ATXN2 effect on RNA with its mitochondrial selectivity, 2) advanced diagnostic procedures in SCA2 patients via blood RNAseq, and 3) supported the putative benefit of preventive therapy in ALS / SCA2 patients via hypercaloric high-carbohydrate diet.

Projektbezogene Publikationen (Auswahl)

• Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet. 2011 May 1;20(9):1697-700
  Lee T, Li YR, Ingre C, Weber M, Grehl T, Gredal O, de Carvalho M, Meyer T, Tysnes OB, Auburger G, Gispert S, Bonini NM, Andersen PM, Gitler AD
  
• Saccadic latency is prolonged in Spinocerebellar Ataxia type 2 and correlates with the frontal-executive dysfunctions. J Neurol Sci. 2011 Jul 15;306(1-2):103-7
  Rodríguez-Labrada R, Velázquez-Pérez L, Seigfried C, Canales-Ochoa N, Auburger G, Medrano- Montero J, Sánchez-Cruz G, Aguilera-Rodríguez R, Laffita-Mesa J, Vázquez-Mojena Y, Verdecia-Ramirez M, Motta M, Quevedo-Batista Y
  
• Sleep disorders in spinocerebellar ataxia type 2 patients. Neurodegener Dis. 2011;8(6):447-54
  Velázquez-Pérez L, Voss U, Rodríguez-Labrada R, Auburger G, Canales Ochoa N, Sánchez Cruz G, Galicia Polo L, Haro Valencia R, Aguilera Rodríguez R, Medrano Montero J, Laffita Mesa JM, Tuin I
  
• Spinocerebellar ataxia type 2 (SCA2): identification of early brain degeneration in one monozygous twin in the initial disease stage. Cerebellum. 2011 Jun;10(2):245-53
  Hoche F, Balikó L, den Dunnen W, Steinecker K, Bartos L, Sáfrány E, Auburger G, Deller T, Korf HW, Klockgether T, Rüb U, Melegh B
  
• ATXN2 and its neighbouring gene SH2B3 are associated with increased ALS risk in the Turkish population. PLoS One. 2012;7(8):e42956
  Lahut S, Ömür Ö, Uyan Ö, Ağım ZS, Özoğuz A, Parman Y, Deymeer F, Oflazer P, Koç F, Özçelik H, Auburger G, Başak AN
  
• ATXN2-CAG42 sequesters PABPC1 into insolubility and induces FBXW8 in cerebellum of old ataxic knock-in mice. PLoS Genet. 2012;8(8):e1002920
  Damrath E, Heck MV, Gispert S, Azizov M, Nowock J, Seifried C, Rüb U, Walter M, Auburger G
  
• Pathoanatomy of cerebellar degeneration in spinocerebellar ataxia type 2 (SCA2) and type 3 (SCA3). Cerebellum. 2012 Sep;11(3):749-60
  Scherzed W, Brunt ER, Heinsen H, de Vos RA, Seidel K, Bürk K, Schöls L, Auburger G, Del Turco D, Deller T, Korf HW, den Dunnen WF, Rüb U
  
• Spinocerebellar ataxia type 2. Handb Clin Neurol. 2012;103:423-36
  Auburger GW
  
• The modulation of Amyotrophic Lateral Sclerosis risk by ataxin-2 intermediate polyglutamine expansions is a specific effect. Neurobiol Dis. 2012 Jan;45(1):356-61
  Gispert S, Kurz A, Waibel S, Bauer P, Liepelt I, Geisen C, Gitler AD, Becker T, Weber M, Berg D, Andersen PM, Krüger R, Riess O, Ludolph AC, Auburger G
  
• Ataxin-2 modulates the levels of Grb2 and SRC but not Ras signaling. J Mol Neurosci. 2013 Sep;51(1):68-81
  Drost J, Nonis D, Eich F, Leske O, Damrath E, Brunt ER, Lastres-Becker I, Heumann R, Nowock J, Auburger G
  
• Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7. Prog Neurobiol. 2013 May;104:38-66
  Rüb U, Schöls L, Paulson H, Auburger G, Kermer P, Jen JC, Seidel K, Korf HW, Deller T
  
• Estimation of survival in spinocerebellar ataxia type 2 Cuban patients. Clin Genet. 2013 Mar;83(3):293-4
  Almaguer-Mederos LE, Aguilera Rodríguez R, González Zaldivar Y, Almaguer Gotay D, Cuello Almarales D, Laffita Mesa J, Vázquez Mojena Y, Zayas Feria P, Auburger G, Gispert S, Velásquez Pérez L
  
• 12q24 locus association with type 1 diabetes: SH2B3 or ATXN2? World J Diabetes. 2014 Jun 15;5(3):316-27
  Auburger G, Gispert S, Lahut S, Omür O, Damrath E, Heck M, Başak N
  
• Dysregulated expression of lipid storage and membrane dynamics factors in Tia1 knockout mouse nervous tissue. Neurogenetics. 2014 May;15(2):135-44
  Heck MV, Azizov M, Stehning T, Walter M, Kedersha N, Auburger G
  
• Both ubiquitin ligases FBXW8 and PARK2 are sequestrated into insolubility by ATXN2 PolyQ expansions, but only FBXW8 expression is dysregulated. PLoS One. 2015 Mar 19;10(3):e0121089
  Halbach MV, Stehning T, Damrath E, Jendrach M, Şen NE, Başak AN, Auburger G
  
• Genetic ablation of ataxin-2 increases several global translation factors in their transcript abundance but decreases translation rate. Neurogenetics. 2015 Jul;16(3):181-92
  Fittschen M, Lastres-Becker I, Halbach MV, Damrath E, Gispert S, Azizov M, Walter M, Müller S, Auburger G
  
• No parkinsonism in SCA2 and SCA3 despite severe neurodegeneration of the dopaminergic substantia nigra. Brain. 2015 Nov;138(Pt 11):3316-26
  Schöls L, Reimold M, Seidel K, Globas C, Brockmann K, Karsten Hauser T, Auburger G, Bürk K, den Dunnen W, Reischl G, Korf HW, Brunt ER, Rüb U