TY - JOUR
T1 - A Novel SCA3 Knock-in Mouse Model Mimics the Human SCA3 Disease Phenotype Including Neuropathological, Behavioral, and Transcriptional Abnormalities Especially in Oligodendrocytes
AU - Haas, Eva
AU - Incebacak, Rana D.
AU - Hentrich, Thomas
AU - Huridou, Chrisovalantou
AU - Schmidt, Thorsten
AU - Casadei, Nicolas
AU - Maringer, Yacine
AU - Bahl, Carola
AU - Zimmermann, Frank
AU - Mills, James D.
AU - Aronica, Eleonora
AU - Riess, Olaf
AU - Schulze-Hentrich, Julia M.
AU - Hübener-Schmid, Jeannette
N1 - Funding Information: The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007-2013) under grant agreement 2012-305121 “Integrated European -omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS).” Further support was received from JPND joint program for neurodegenerative disease, funding the project “Identification of genes that modulate the severity of neurodegenerative diseases (NeuroGem)” (FKZ01ED1507), the Netherlands Organization for Health Research and Development (ZonMw; AE, JM) and was supported by the Deutsche Forschungsgemeinschaft, DFG through the funding of the NGS Competence Center Tübingen (NCCT-DFG, project 407494995). We acknowledge support by Deutsche Forschungsgemeischaft and Open Access Publishing Fund of University of Tübingen. Publisher Copyright: © 2021, The Author(s).
PY - 2021
Y1 - 2021
N2 - Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.
AB - Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide, caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyglutamine (polyQ)-expansion in the corresponding protein. The disease is characterized by neuropathological, phenotypical, and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed for a better understanding of the disease pathomechanisms. Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing a heterozygous or homozygous expansion of 304 CAACAGs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. We compared neuropathological, and behavioral features of the new knock-in model with the in SCA3 research mostly used YAC84Q mouse model. Further, we compared transcriptional changes found in cerebellar samples of the SCA3 knock-in mice and post-mortem human SCA3 patients. The novel knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, the mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes.
KW - Ataxin-3
KW - Knock-in mouse model
KW - Machado-Joseph disease
KW - Myelinating oligodendrocytes
KW - Spinocerebellar ataxia type 3
UR - http://www.scopus.com/inward/record.url?scp=85118289732&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s12035-021-02610-8
DO - https://doi.org/10.1007/s12035-021-02610-8
M3 - Article
C2 - 34716557
SN - 0893-7648
JO - Molecular neurobiology
JF - Molecular neurobiology
ER -