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

• DOI: 10.1523/jneurosci.1882-20.2021
• Publication Date: 2021-04-22T19:56:42Z
• Authors: Anna Niewiadomska...; Frédéric Doussau; Jean-Baptiste Perot; Michel J. Roux; Celine Keime; Antoine Hache; Françoise Piguet; Ariana Novati; Chantal Weber; Binnaz Yalcin; Hamid Meziane; Marie-France Champy; Erwan Grandgirard; Alice Karam; Nadia Messaddeq; Aurélie Eisenmann; Emmanuel Brouillet; Hoa Huu Phuc Nguyen; Julien Flament; Philippe Isope; Yvon Trottier
• Keywords: Male; 0301 basic medicine; 0303 health sciences; [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology; Down-Regulation; Mice; Purkinje Cells; 03 medical and health sciences; Cerebellum; Animals; Spinocerebellar Ataxias; Female; Gene Knock-In Techniques; Transcriptome

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease mainly characterized by motor incoordination because of progressive cerebellar degeneration. SCA7 caused polyglutamine expansion in ATXN7, a subunit the transcriptional coactivator SAGA, which harbors histone modification activities. Polyglutamine expansions specific proteins are also responsible for SCA1-SCA3, SCA6, and SCA17; however, converging diverging pathomechanisms remain poorly understood. Using new knock-in mouse, 140Q/5Q , we analyzed gene expression cerebellum assigned deregulation to cell types using published datasets. Gene affects all types, although at variable degree, correlates with alterations SAGA-dependent epigenetic marks. Purkinje cells (PCs) far most affected neurons show reduced 83 cell-type identity genes, including these critical their spontaneous firing activity synaptic functions. PC downregulation precedes morphologic alterations, pacemaker dysfunction, incoordination. Strikingly, genes downregulated have decreased SCA1 SCA2 mice, revealing common signature involving cGMP-PKG phosphatidylinositol signaling pathways LTD. Our study thus points out molecular targets therapeutic development, may prove beneficial several SCAs. Furthermore, that males females exhibit major features observed patients, damage, cerebral atrophy, peripheral nerves pathology, photoreceptor dystrophy, account impairment behavior, motor, visual mice represent accurate model investigation different aspects pathogenesis. SIGNIFICANCE STATEMENT one forms SCAs degeneration proteins. The ATXN7 involved SAGA complex. To understand SCA7, determined type-specific mouse cerebellum. We found large subset neuronal same models two other Thus, our work reveals shared among uncovers potential treatment.