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

Autor: Canet-Pons J; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany., Sen NE; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany; Faculty of Biosciences, Goethe University, 60438 Frankfurt am Main, Germany., Arsović A; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany., Almaguer-Mederos LE; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany; Center for Investigation and Rehabilitation of Hereditary Ataxias (CIRAH), Holguín, Cuba., Halbach MV; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany., Key J; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany; Faculty of Biosciences, Goethe University, 60438 Frankfurt am Main, Germany., Döring C; Dr. Senckenberg Institute of Pathology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany., Kerksiek A; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Nordrhein-Westfalen, Germany., Picchiarelli G; UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France., Cassel R; UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France., René F; UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France., Dieterlé S; UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France., Fuchs NV; Host-Pathogen Interactions, Paul-Ehrlich-Institute, 63225 Langen, Germany., König R; Host-Pathogen Interactions, Paul-Ehrlich-Institute, 63225 Langen, Germany., Dupuis L; UMRS-1118 INSERM, Faculty of Medicine, University of Strasbourg, 67000 Strasbourg, France., Lütjohann D; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53127 Bonn, Nordrhein-Westfalen, Germany., Gispert S; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany., Auburger G; Experimental Neurology, Medical Faculty, Goethe University, 60590 Frankfurt am Main, Germany. Electronic address: auburger@em.uni-frankfurt.de.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2021 May; Vol. 152, pp. 105289. Date of Electronic Publication: 2021 Feb 10.
DOI: 10.1016/j.nbd.2021.105289
Abstrakt: 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.
(Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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