Accumulation of FAM98B and tRNA-Splicing Ligase Complex Proteins in Neuronal Intranuclear Inclusions in Spinocerebellar ataxia type 4.
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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BibTeX
@misc{gandelman2026accumulation,
title = {{Accumulation of FAM98B and tRNA-Splicing Ligase Complex Proteins in Neuronal Intranuclear Inclusions in Spinocerebellar ataxia type 4.}},
author = {Mandi Gandelman and Karla P. Figueroa and Anton Classen and Daniel R. Scoles and Stefan M. Pulst},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761951},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761951v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Accumulation of FAM98B and tRNA-Splicing Ligase Complex Proteins in Neuronal Intranuclear Inclusions in Spinocerebellar ataxia type 4.
AU - Mandi Gandelman
AU - Karla P. Figueroa
AU - Anton Classen
AU - Daniel R. Scoles
AU - Stefan M. Pulst
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761951
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761951v1
AB - 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.
SN - 2692-8205
ER -