Intercellular Propagation and Aggregate Seeding of Mutant Ataxin-1

Abstract

Intercellular propagation of aggregated protein inclusions along actin-based tunneling nanotubes (TNTs) has been reported as a means of pathogenic spread in Alzheimer’s, Parkinson’s, and Huntington’s diseases. Propagation of oligomeric-structured polyglutamine-expanded ataxin-1 (Atxn1[154Q]) has been reported in the cerebellum of a Spinocerebellar ataxia type 1 (SCA1) knock-in mouse to correlate with disease propagation. In this study, we investigated whether a physiologically relevant polyglutamine-expanded ATXN1 protein (ATXN1[82Q]) could propagate intercellularly. Using a cerebellar-derived live cell model, we observed ATXN1 aggregates form in the nucleus, subsequently form in the cytoplasm, and finally, propagate to neighboring cells along actin-based intercellular connections. Additionally, we observed the facilitation of aggregate-resistant proteins into aggregates given the presence of aggregation-prone proteins within cells. Taken together, our results support a pathogenic role of intercellular propagation of polyglutamine-expanded ATXN1 inclusions.

Nucleus accumbens degeneration in spinocerebellar ataxia type 2: a preliminary study

“…One previous report inferred Wallerian degeneration between the cerebellum and brainstem in SCA2 patients. 27 Another possible explanation for this is the involvement of the intercellular propagation of abnormal polyglutamineexpanded proteins, which has been reported in other polyglutamine disorders such as SCA1 28 and Huntington's disease. 29 In the supratentorial brain, prefrontal cortex, amygdala, and hippocampus project specific information to the NAc.…”

Roles of Nucleic Acids in Protein Folding, Aggregation, and Disease

“…Despite tempting links to other repeat expansion disorders like HD, there remains controversy surrounding the mechanisms of many SCA disorders. , For SCA-1, questions persist regarding whether the polyQ expansion can exit the nucleus and what drives disease pathology. ,− Other SCAs associated with ataxin polyQ expansion disorders also may not necessarily share the same disease mechanisms. , However, despite the complexity, investigating the role of RNA in the aggregation of SCA-related proteins offers a promising avenue for further research and potential treatments.…”

“…189−191 SCA type 1 (SCA1), the first well-characterized SCA, results from CAG repeats in the ATXN1 gene, leading to a polyglutamine expansion in the ataxin-1 protein. 193,195 Ataxin-1 is a gene repressor and functions primarily as a DNA-binding protein, although it can also interact with RNA. 196,197 Studies using ataxin-1 with varying polyQ repeat lengths have demonstrated its ability to bind both polyU and polyG RNA, with a stronger affinity for polyG.…”

“…192−194 Ataxin-1 is primarily found in the nucleus of nervous tissue but is also expressed throughout the body. Like other 193,195 Ataxin-1 is a gene repressor and functions primarily as a DNA-binding protein, although it can also interact with RNA. 196,197 Studies using ataxin-1 with varying polyQ repeat lengths have demonstrated its ability to bind both polyU and polyG RNA, with a stronger affinity for polyG.…”

“…SCA type 1 (SCA1), the first well-characterized SCA, results from CAG repeats in the ATXN1 gene, leading to a polyglutamine expansion in the ataxin-1 protein. − Ataxin-1 is primarily found in the nucleus of nervous tissue but is also expressed throughout the body. Like other polyglutamine expansions, ataxin-1 with a polyglutamine expansion (ataxin-1­[polyQ]) tends to aggregate, with 39 polyQ repeats considered a diseased state. , Ataxin-1 is a gene repressor and functions primarily as a DNA-binding protein, although it can also interact with RNA. , …”