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bioRxiv · 10.64898/2026.10.26.761951

Accumulation of FAM98B and tRNA-Splicing Ligase Complex Proteins in Neuronal Intranuclear Inclusions in Spinocerebellar ataxia type 4.

Gandelman, M.·Figueroa, K. P.·Classen, A.·Scoles, D. R.·Pulst, S. M.
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Abstract

Background and Objectives: Spinocerebellar ataxia type 4 (SCA4) is caused by a GGC-repeat expansion in ZFHX3 encoding an expanded polyglycine tract causing p62- and ubiquitin-positive neuronal intranuclear inclusions (NIIs). In multiple polyglycine diseases NIIs sequester tRNA-splicing ligase complex (tRNA-LC) proteins, causing downstream functional defects linked to neurodegeneration. We assessed the localization of tRNA-LC proteins in SCA4 pontine neurons. Methods: Postmortem brain tissue from a genetically confirmed SCA4 patient was examined across multiple regions using immunofluorescence confocal microscopy for p62, ubiquitin and tRNA-LC proteins FAM98B, RTRAF, and RTCB. Results: In pontine neurons, FAM98B, RTRAF, and RTCB were incorporated into NII, accumulating in a distinct outer layer respective to a ubiquitin inner layer. This redistribution was accompanied by depletion of all three proteins from the soluble nucleoplasm. Discussion: Our findings link SCA4 to a tRNA-LC dysfunction phenotype shared by multiple GGC-repeat disorders, further supporting a unified pathological mechanism in polyglycine diseases.

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Gandelman, M., Figueroa, K. P., Classen, A., Scoles, D. R., Pulst, S. M.. 2026-10-30. Accumulation of FAM98B and tRNA-Splicing Ligase Complex Proteins in Neuronal Intranuclear Inclusions in Spinocerebellar ataxia type 4.. https://doi.org/10.64898/2026.10.26.761951

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