Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

  1. Canet-Pons, Júlia
  2. Sen, Nesli-Ece
  3. Arsović, Aleksandar
  4. Almaguer-Mederos, Luis-Enrique
  5. Halbach, Melanie V.
  6. Key, Jana
  7. Döring, Claudia
  8. Kerksiek, Anja
  9. Picchiarelli, Gina
  10. Cassel, Raphaelle
  11. René, Frédérique
  12. Dieterlé, Stéphane
  13. Fuchs, Nina ORCID logo
  14. König, Renate ORCID logo
  15. Dupuis, Luc
  16. Lütjohann, Dieter
  17. Gispert, Suzana
  18. Auburger, Georg

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1000 Titel
  • Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression
1000 Autor/in
  1. Canet-Pons, Júlia |
  2. Sen, Nesli-Ece |
  3. Arsović, Aleksandar |
  4. Almaguer-Mederos, Luis-Enrique |
  5. Halbach, Melanie V. |
  6. Key, Jana |
  7. Döring, Claudia |
  8. Kerksiek, Anja |
  9. Picchiarelli, Gina |
  10. Cassel, Raphaelle |
  11. René, Frédérique |
  12. Dieterlé, Stéphane |
  13. Fuchs, Nina |
  14. König, Renate |
  15. Dupuis, Luc |
  16. Lütjohann, Dieter |
  17. Gispert, Suzana |
  18. Auburger, Georg |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-02-10
1000 Erschienen in
1000 Quellenangabe
  • 152(2021):105289
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1016/j.nbd.2021.105289 |
1000 Ergänzendes Material
  • https://www.sciencedirect.com/science/article/pii/S0969996121000383#p0350 |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology. Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1 and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies.
1000 Sacherschließung
lokal Tauopathy
lokal Olivo-ponto-cerebellar atrophy
lokal Demyelination
lokal Steroidogenesis
lokal Leukoencephalopathy
gnd 4171577-9 Neuroanatomie
lokal Neuroinfammation
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/Q2FuZXQtUG9ucywgSsO6bGlh|https://frl.publisso.de/adhoc/uri/U2VuLCBOZXNsaS1FY2U=|https://frl.publisso.de/adhoc/uri/QXJzb3ZpxIcsIEFsZWtzYW5kYXI=|https://frl.publisso.de/adhoc/uri/QWxtYWd1ZXItTWVkZXJvcywgTHVpcy1FbnJpcXVl|https://frl.publisso.de/adhoc/uri/SGFsYmFjaCwgTWVsYW5pZSBWLg==|https://frl.publisso.de/adhoc/uri/S2V5LCBKYW5h|https://frl.publisso.de/adhoc/uri/RMO2cmluZywgQ2xhdWRpYQ==|https://frl.publisso.de/adhoc/uri/S2Vya3NpZWssIEFuamE=|https://frl.publisso.de/adhoc/uri/UGljY2hpYXJlbGxpLCBHaW5h|https://frl.publisso.de/adhoc/uri/Q2Fzc2VsLCBSYXBoYWVsbGU=|https://frl.publisso.de/adhoc/uri/UmVuw6ksIEZyw6lkw6lyaXF1ZQ==|https://frl.publisso.de/adhoc/uri/RGlldGVybMOpLCBTdMOpcGhhbmU=|https://orcid.org/0000-0003-4175-0740|https://orcid.org/0000-0003-4882-9179|https://frl.publisso.de/adhoc/uri/RHVwdWlzLCBMdWM=|https://frl.publisso.de/adhoc/uri/TMO8dGpvaGFubiwgRGlldGVy|https://frl.publisso.de/adhoc/uri/R2lzcGVydCwgU3V6YW5h|https://frl.publisso.de/adhoc/uri/QXVidXJnZXIsIEdlb3Jn
1000 Label
1000 Förderer
  1. Deutsche Forschungsgemeinschaft |
1000 Fördernummer
  1. AU96/11-1 ; 11-3
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  1. -
1000 Dateien
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  1. 1000 joinedFunding-child
    1000 Förderer Deutsche Forschungsgemeinschaft |
    1000 Förderprogramm -
    1000 Fördernummer AU96/11-1 ; 11-3
1000 Objektart article
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1000 Erstellt am 2022-02-22T14:37:50.065+0100
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1000 Zuletzt bearbeitet Thu Feb 24 10:31:13 CET 2022
1000 Objekt bearb. Thu Feb 24 10:30:43 CET 2022
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