Abstract
Spinocerebellar ataxia type 1 (SCA1) is an adult-onset neurodegenerative disorder characterized by motor incoordination, mild cognitive decline, respiratory dysfunction, and early lethality. It is caused by the expansion of the polyglutamine (polyQ) tract in Ataxin-1 (ATXN1), which stabilizes the protein, leading to its toxic accumulation in neurons. Previously, we showed that serine 776 (S776) phosphorylation is critical for ATXN1 stability and contributes to its toxicity in cerebellar Purkinje cells. Still, the therapeutic potential of disrupting S776 phosphorylation on noncerebellar SCA1 phenotypes remains unstudied. Here, we report that abolishing S776 phosphorylation specifically on the polyQ-expanded ATXN1 of SCA1-knockin mice reduces ATXN1 throughout the brain and not only rescues the cerebellar motor incoordination but also improves respiratory function and extends survival while not affecting the hippocampal learning and memory deficits. As therapeutic approaches are likely to decrease S776 phosphorylation on polyQ-expanded and WT ATXN1, we further disrupted S776 phosphorylation on both alleles and observed an attenuated rescue, demonstrating a potential protective role of WT allele. This study not only highlights the role of S776 phosphorylation to regulate ATXN1 levels throughout the brain but also suggests distinct brain region–specific disease mechanisms and demonstrates the importance of developing allele-specific therapies for maximal benefits in SCA1.
Highlights
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats encoding the polyglutamine tract in Ataxin-1 (ATXN1) [1, 2]
As the hATXN1[82Q] protein was only expressed in cerebellar Purkinje cells, it remains unclear in which other tissues serine 776 (S776) is phosphorylated and if its disruption could reduce ATXN1 levels in all brain regions affected in SCA1
We evaluated the potential of targeting ATXN1 S776 phosphorylation as a therapeutic entry point for SCA1
Summary
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of CAG repeats encoding the polyglutamine (polyQ) tract in Ataxin-1 (ATXN1) [1, 2]. Disruption of S776 phosphorylation in a transgenic SCA1 mouse model overexpressing human ATXN1[82Q] exclusively in cerebellar Purkinje cells (PCP2-hATXN1[82Q]) reduced hATXN1[82Q] transgene protein levels and improved the cerebellar motor coordination phenotypes [9]. This seminal work demonstrated that disruption of S776 phosphorylation might serve as a potential therapeutic entry point for SCA1
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