Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

Won Seok Lee, Ismael Al-Ramahi, Hyun Hwan Jeong, Youjin Jang, Tao Lin, Carolyn J. Adamski, Laura A. Lavery, Smruti Rath, Ronald Richman, Vitaliy V. Bondar, Elizabeth Alcala, Jean Pierre Revelli, Harry T. Orr, Zhandong Liu, Juan Botas, Huda Y. Zoghbi

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4 Scopus citations


Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.

Original languageEnglish (US)
Article numbere156616
JournalJournal of Clinical Investigation
Issue number9
StatePublished - May 2 2022

Bibliographical note

Funding Information:
We thank M. Rousseaux and J. Kim for their input into the cell-based screen and validation pipelines; L. Nitschke for providing the inducible Daoy cell lines; A. Tewari for assistance with stereotaxic injection; A. Bajic from Human Neuronal Differentiation Core for general support of culturing human neurons; V. Shakkottai at Michigan Brain Bank (5P30 AG053760 University of Michigan Alzheimer’s Disease Core Center) and L. Ranum at the Center for NeuroGenetics at University of Florida and National Ataxia Foundation for sharing control and SCA1 patient tissue slides, respectively; Genomic and RNA Profiling Core at BCM for the Illumina sequencing; J. Barrish and J. Hicks from the Texas Children’s Hospital electron microscopy core for assistance with using SEM; and members of the Zoghbi lab for input on the manuscript. This project was supported by grant NIH/NINDS R37NS027699 to HYZ and NIH/NIA R01AG057339 to JB, NIH/ NINDS R01-NS045667-17 to HTO, NIH/NIGMS R01GM120033 to ZL, NIH R21NS096395, and the Darrell K Royal Research Fund for Alzheimer’s Disease to IAR. WSL was a Howard Hughes Medical Institute International Student Research fellow and HYZ is a Howard Hughes Medical Institute investigator. This project was also supported by the JPB Foundation MR-2020-2156 and by the IDDRC at Baylor College of Medicine (15P50HD103555—Behavioral Core) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the NIH.

Publisher Copyright:
2022, Lee et al.


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