Disrupting ATXN1 Nuclear Localization in a Knock-in SCA1 Mouse Model Improves a Spectrum of SCA1-Like Phenotypes and their Brain Region Associated Transcriptomic Profiles
Orr, H. T.; Handler, H. P.; Duvick, L.; Mitchell, J.; Cvetanovic, M.; Reighard, M.; Soles, A.; Rainwater, O.; Serres, S.; Nichols-Meade, T.; Coffin, S. L.; Yoou, Y.; Ruis, B.; Ocallaghan, B.; Henzler, C.; Zoghbi, H. Y.
Show abstract
Spinocerebellar ataxia type 1 (SCA1) is a dominant trinucleotide repeat neurodegenerative disease characterized by motor dysfunction, cognitive impairment, and premature death. Degeneration of cerebellar Purkinje cells is a frequent and prominent pathological feature of SCA1. We previously showed that transport of ATXN1 to Purkinje cell nuclei is required for pathology, where mutant ATXN1 alters transcription. To examine the role of ATXN1 nuclear localization broadly in SCA1-like disease pathogenesis, CRISPR-Cas9 was used to develop a mouse with the amino acid alteration (K772T) in the nuclear localization sequence of the expanded ATXN1 protein. Characterization of these mice indicates proper nuclear localization of mutant ATXN1 contributes to many disease-like phenotypes including motor dysfunction, cognitive deficits, and premature lethality. RNA sequencing analysis of genes whose expression was corrected to WT levels in Atxn1175QK772T/2Q mice indicates that transcriptomic aspects of SCA1 pathogenesis differ between the cerebellum, brainstem, cerebral cortex, hippocampus, and striatum.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- TDP-43-M323K causes abnormal brain development and progressive cognitive and motor deficits associated with mislocalised and increased levels of TDP-43. 95%
- Epilepsy and neurobehavioral abnormalities in mice with a KCNB1 pathogenic variant that alters conducting and non-conducting functions of KV2.1 94%
- Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice 94%
Similar papers in this journal
- Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1 96%
- Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice 96%
- Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat 93%
Similar papers in this journal
- A novel, ataxic mouse model of Ataxia Telangiectasia caused by a clinically relevant nonsense mutation 96%
- TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons 96%
- Cell autonomous role of leucine-rich repeat kinase in protection of dopaminergic neuron survival 94%
Similar papers in this journal
- Transgenic mice expressing human alpha-synuclein in noradrenergic neurons develop locus coeruleus pathology and non-motor features of Parkinson's disease 94%
- Impaired oligodendrocyte maturation is an early feature in SCA3 disease pathogenesis 94%
- Progressive excitability changes in the medial entorhinal cortex in the 3xTg mouse model of Alzheimer's disease pathology 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.