Cerebellar axonopathy in Shivers horses identified by spatial transcriptomic and proteomic analyses.
Authors: Valberg Stephanie J, Williams Zoë J, Henry Marisa L, Finno Carrie J
Journal: Journal of veterinary internal medicine
Summary
Shivers, a condition affecting hindlimb movement during backing, has long been suspected to involve degeneration of Purkinje cell axons in the cerebellum, yet the molecular mechanisms underlying this neurological disorder remain poorly characterised. Valberg and colleagues employed spatial transcriptomics and proteomic analysis on tissue samples from five affected and four control horses, systematically comparing gene and protein expression within the lateral cerebellar hemisphere—the region containing Purkinje cell axons—rather than the neuronal cell bodies themselves. Whilst gene expression patterns in the Purkinje cell soma appeared unremarkable, the white matter region housing axons showed marked dysregulation, with 455 differentially expressed genes (350 downregulated, 105 upregulated) and particularly striking enrichment in the Toll-Like Receptor 4 inflammatory cascade, indicating active neuroinflammation. Protein analysis revealed 50 differentially expressed proteins, with downregulation of critical axonal structural components including intermediate filaments, myelin proteins, and cytoskeletal elements, alongside reduced Na/K ATPase expression—findings consistent with progressive axonal deterioration without substantial soma damage. These molecular changes provide objective support for axonopathy as the pathological basis of Shivers and may eventually guide development of therapeutics targeting neuroinflammatory pathways, whilst highlighting the importance of examining axonal compartments separately when investigating neurodegenerative conditions in horses.
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Practical Takeaways
- •Shivers is confirmed as a primary axonal disease affecting cerebellar Purkinje cell projections, not a soma-level pathology, which may inform future therapeutic targeting strategies
- •The neuroinflammatory signature (TLR4 cascade activation) suggests potential anti-inflammatory approaches could be investigated as therapeutic options for affected horses
- •Recognition that this is a degenerative neurological condition supports realistic expectations for management and prognosis in diagnosed horses
Key Findings
- •Spatial transcriptomics revealed 455 differentially expressed genes in cerebellar white matter between Shivers and control horses, with significant enrichment of the TLR4 neuroinflammatory cascade
- •Proteomic analysis identified 27 downregulated proteins in Shivers horses, particularly axonal structural proteins including intermediate filaments, myelin, and cytoskeletal components
- •Gene expression differences were evident in axon-containing white matter but not in Purkinje cell soma, supporting selective axonal degeneration as the pathological hallmark
- •Loss of Na/K ATPase and upregulation of extracellular matrix proteins suggest active axonal dysfunction and remodeling in Shivers pathogenesis