Abstract
Mutant huntingtin (mHtt) proteins interact to form aggregates, disrupting cellular functions including transcriptional dysregulation and iron imbalance in patients with Huntington’s disease (HD) and mouse disease models. Previous studies have indicated that mHtt may lead to abnormal iron homeostasis by upregulating the expression of iron response protein 1 (IRP1) in the striatum and cortex of N171-82Q HD transgenic mice, as well as in HEK293 cells expressing the N-terminal fragment of mHtt containing 160 CAG repeats. However, the mechanism underlying the upregulation of IRP1 remains unclear. We investigated the levels and phosphorylation status of signal transducer and activator of transcription 5 (STAT5) in the brains of N171-82Q HD transgenic mice using immunohistochemistry staining. We also assessed the nuclear localization of STAT5 protein through western blot and immunofluorescence, and measured the relative RNA expression levels of STAT5 and IRP1 using RT-PCR in both N171-82Q HD transgenic mice and HEK293 cells expressing the N-terminal fragment of huntingtin. Our findings demonstrate that the transcription factor STAT5 regulates the transcription of the IPR1 gene in HEK293 cells. Notably, both the brains of N171-82Q mice and 160Q HEK293 cells exhibited increased nuclear content of STAT5, despite unchanged total STAT5 expression. These results suggest that mHtt promotes the nuclear translocation of STAT5, leading to enhanced expression of IRP1. The nuclear translocation of STAT5 initiates abnormal iron homeostatic pathways, characterized by elevated IRP1 expression, increased levels of transferrin and transferrin receptor, and iron accumulation in the brains of HD mice. These findings provide valuable insights into potential therapeutic strategies targeting iron homeostasis in HD.
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Data availability
The data used to support the findings of this study are available from the corresponding author upon request.
Abbreviations
- HD:
-
Huntington’s disease
- STAT5:
-
Signal transducer and activator of transcription 5
- mHTT:
-
Mutant huntingtin
- TfR:
-
Transferrin receptors
- Tf:
-
Transferrin
- IRPs:
-
Iron regulatory proteins
- IREs:
-
Iron-responsive elements
- MRI:
-
Magnetic resonance imaging
- WT:
-
Wild type
- GP:
-
Globus pallidus
- SN:
-
Substantia nigra
- ROS:
-
Reactive oxygen species
- GP:
-
Globus pallidus
- SN:
-
Substantia nigra
- DAB:
-
Diaminobenzidine
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This work was supported by Zhongnan Hospital of Wuhan University Science, Technology and Innovation Seed Fund, Project (NO. znpy 2019069). And supported by Zhongnan Hospital of Wuhan University Discipline Platform Construction Project (NO. PTXM 2023026).
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Li Niu, Wei Zeng, experiments concept, manuscript drafting; Li Niu, experiments performing; Yongze Zhou, Jie Wang; samples collections and data analysis. All the authors have read and approved the final version of the manuscript and agreed to be accountable for all aspects of the work.
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Niu, L., Zhou, Y., Wang, J. et al. Nuclear translocation of STAT5 initiates iron overload in huntington’s disease by up-regulating IRP1 expression. Metab Brain Dis 39, 559–567 (2024). https://doi.org/10.1007/s11011-024-01340-9
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DOI: https://doi.org/10.1007/s11011-024-01340-9