SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2

Autor: Chantal Weber, Nadia Messaddeq, Antoine Hache, Frédéric Doussau, Aurélie Eisenmann, Anna Niewiadomska-Cimicka, Marie-France Champy, Yvon Trottier, Michel Roux, Julien Flament, Erwan Grandgirard, Hamid Meziane, Céline Keime, Binnaz Yalcin, Philippe Isope, Alice Karam, Jean-Baptiste Perot, Hoa Huu Phuc Nguyen, Françoise Piguet, Emmanuel Brouillet, Ariana Novati
Přispěvatelé: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institut Clinique de la Souris, Institute of Genetics and Molecular and Cellular Biology (IGBMC), INSERM-U964, Strasbourg University, Illkirch, ANR-15-JPWG-0008,ModelPolyQ,Advanced models of polyglutamine disorders -HD, SCA2, SCA3, SCA7-(2015), ANR-17-RAR3-0008,TreatPolyQ,Allele-specific lowering of mutant polyQ proteins as treatment for Huntington disease, spinocerebellar ataxia type 3 and spinocerebellar ataxia type 7(2017), ANR-18-CE12-0026,SAGA-Retina,Rôle du complexe co-activateur SAGA dans la transcription au cours de la différenciation cellulaire chez les mammifères(2018), ANR-15-CE37-0001,CeMod,Traitement modulaire de l'information dans le cervelet et mouvements anormaux(2015), ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 643417,H2020,H2020-HCO-2014,JPco-fuND(2015), Roux, Michel, PHENOMIN, GIE CERBM
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal of Neuroscience
Journal of Neuroscience, 2021, 41 (22), pp.4910-4936. ⟨10.1523/JNEUROSCI.1882-20.2021⟩
The journal of neuroscience
J Neurosci
Journal of Neuroscience, Society for Neuroscience, 2021, 41 (22), pp.4910-4936. ⟨10.1523/JNEUROSCI.1882-20.2021⟩
ISSN: 0270-6474
1529-2401
Popis: Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 is caused by polyglutamine expansion in ATXN7, a subunit of the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions in specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, the converging and diverging pathomechanisms remain poorly understood. Using a new SCA7 knock-in mouse, SCA7140Q/5Q, we analyzed gene expression in the cerebellum and assigned gene deregulation to specific cell types using published datasets. Gene deregulation affects all cerebellar cell types, although at variable degree, and correlates with alterations of SAGA-dependent epigenetic marks. Purkinje cells (PCs) are by far the most affected neurons and show reduced expression of 83 cell-type identity genes, including these critical for their spontaneous firing activity and synaptic functions. PC gene downregulation precedes morphologic alterations, pacemaker dysfunction, and motor incoordination. Strikingly, most PC genes downregulated in SCA7 have also decreased expression in SCA1 and SCA2 mice, revealing converging pathomechanisms and a common disease signature involving cGMP-PKG and phosphatidylinositol signaling pathways and LTD. Our study thus points out molecular targets for therapeutic development, which may prove beneficial for several SCAs. Furthermore, we show that SCA7140Q/5Qmales and females exhibit the major disease features observed in patients, including cerebellar damage, cerebral atrophy, peripheral nerves pathology, and photoreceptor dystrophy, which account for progressive impairment of behavior, motor, and visual functions. SCA7140Q/5Qmice represent an accurate model for the investigation of different aspects of SCA7 pathogenesis.SIGNIFICANCE STATEMENTSpinocerebellar ataxia 7 (SCA7) is one of the several forms of inherited SCAs characterized by cerebellar degeneration because of polyglutamine expansion in specific proteins. The ATXN7 involved in SCA7 is a subunit of SAGA transcriptional coactivator complex. To understand the pathomechanisms of SCA7, we determined the cell type-specific gene deregulation in SCA7 mouse cerebellum. We found that the Purkinje cells are the most affected cerebellar cell type and show downregulation of a large subset of neuronal identity genes, critical for their spontaneous firing and synaptic functions. Strikingly, the same Purkinje cell genes are downregulated in mouse models of two other SCAs. Thus, our work reveals a disease signature shared among several SCAs and uncovers potential molecular targets for their treatment.
Databáze: OpenAIRE
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