Purkinje-Enriched snRNA-seq in SCA7 Cerebellum Reveals Zebrin Identity Loss as a Central Feature of Polyglutamine Ataxias
Bartelt, L. C.; Switonski, P. M.; Adamek, G.; Carvalho, J.; Duvick, L. A.; Jarrah, S. I.; McLoughlin, H. S.; Scoles, D. R.; Pulst, S. M.; Orr, H. T.; Hull, C.; Lowe, C. B.; La Spada, A. R.
Show abstract
Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder caused by a CAG-polyglutamine repeat expansion. SCA7 patients display a striking loss of Purkinje cell (PC) neurons with disease progression; however, PCs are rare, making them difficult to characterize. We developed a PC nuclei enrichment protocol and applied it to single-nucleus RNA-seq of a SCA7 knock-in mouse model. Our results unify prior observations into a central mechanism of cell identity loss, impacting both glia and PCs, driving accumulation of inhibitory synapses and altered PC spiking. Zebrin-II subtype dysregulation is the predominant signal in PCs, leading to complete loss of zebrin-II striping at motor symptom onset in SCA7 mice. We show this zebrin-II subtype degradation is shared across Polyglutamine Ataxia mouse models and SCA7 patients. It has been speculated that PC subtype organization is critical for cerebellar function, and our results suggest that a breakdown of zebrin-II parasagittal striping is pathological.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- The patient-specific mouse model with Foxg1 frameshift mutation provides insights into the pathophysiology of FOXG1 syndrome 95%
- Mitotic Block and Epigenetic Repression Underlie Neurodevelopmental Defects and Neurobehavioral Deficits in Congenital Heart Disease 95%
- The transcriptional response of cortical neurons to concussion reveals divergent fates after injury 95%
Similar papers in this journal
- Comprehensive multiomic profiling of somatic mutations in malformations of cortical development 93%
- Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology 93%
- The impact of rare protein coding genetic variation on adult cognitive function 93%
Similar papers in this journal
- Molecular and spatial transcriptomic classification of midbrain dopamine neurons and their alterations in a LRRK2G2019S model of Parkinson's disease 94%
- TTBK2 and primary cilia are essential for the connectivity and survival of cerebellar Purkinje neurons 94%
- PTBP1 Depletion in Mature Astrocytes Reveals Distinct Splicing Alterations Without Neuronal Features 94%
Similar papers in this journal
- Altered Capicua expression drives regional Purkinje neuron vulnerability through ion channel gene dysregulation in Spinocerebellar ataxia type 1 95%
- Slc9a6 mutation causes Purkinje cell loss and ataxia in the shaker rat 93%
- Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons 92%
Similar papers in this journal
- Endocytic adaptor AP-2 maintains Purkinje cell function by balancing cerebellar parallel and climbing fiber synapses 94%
- ALS molecular subtypes are a combination of cellular, genetic, and pathological features learned by deep multiomics classifiers 94%
- Compensation between FOXP transcription factors maintains proper striatal function 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.