Back to Search
Start Over
SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2
SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2
- Source :
- 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⟩
- Publication Year :
- 2021
- Publisher :
- HAL CCSD, 2021.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Cerebellum
Pathology
medicine.medical_specialty
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Purkinje cell
Down-Regulation
Biology
03 medical and health sciences
Mice
Purkinje Cells
0302 clinical medicine
Downregulation and upregulation
Gene expression
medicine
Cerebellar Degeneration
Animals
Spinocerebellar Ataxias
Epigenetics
Gene Knock-In Techniques
Research Articles
ComputingMilieux_MISCELLANEOUS
General Neuroscience
[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
Dystrophy
medicine.disease
030104 developmental biology
medicine.anatomical_structure
Spinocerebellar ataxia
Female
Transcriptome
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 02706474 and 15292401
- Database :
- OpenAIRE
- Journal :
- 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⟩
- Accession number :
- edsair.doi.dedup.....ea85b30c6dc1216aedad93c59f1bc02e
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.1882-20.2021⟩