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

NEUROBIOLOGY OF DISEASE

卷:152

Article

Canet-Pons, Julia¹  Sen, Nesli-Ece^1,2  Arsovic, Aleksandar¹  Almaguer-Mederos, Luis-Enrique^1,3  Halbach, Melanie V.¹  Key, Jana^1,2  Doering, Claudia⁴  Kerksiek, Anja⁵  Picchiarelli, Gina⁶  Cassel, Raphaelle⁶  Rene, Frederique⁶  Dieterle, Stephane⁶  Fuchs, Nina V.⁷  Koenig, Renate⁷  Dupuis, Luc⁶  Luetjohann, Dieter⁵  Gispert, Suzana¹  Auburger, Georg¹ 

[1] Goethe Univ, Fac Med, Expt Neurol, D-60590 Frankfurt, Germany

[2] Goethe Univ, Fac Biosci, D-60438 Frankfurt, Germany

[3] Ctr Invest & Rehabil Hereditary Ataxias CIRAH, Holguin, Cuba

[4] Goethe Univ, Fac Med, Dr Senckenberg Inst Pathol, D-60590 Frankfurt, Germany

[5] Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, D-53127 Bonn, Nordrhein Westf, Germany

[6] Univ Strasbourg, INSERM, Fac Med, UMRS 1118, F-67000 Strasbourg, France

[7] Paul Ehrlich Inst, Host Pathogen Interact, D-63225 Langen, Germany

关键词: Olivo-ponto-cerebellar atrophy;    Tauopathy;    Neuroinflammation;    Demyelination;    Leukoencephalopathy;    Steroidogenesis;   

DOI  :  10.1016/j.nbd.2021.105289

来源: Elsevier

【 摘 要 】

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.