1. A novel function for α-synuclein as a regulator of NCK2 in olfactory bulb: implications for its role in olfaction
- Author
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Jing Ren, Chao Wu, Mengxia Zeng, Mingqin Qu, Ge Gao, Ning Chen, Jingjing Yue, Yuwen Jiang, Tongfei Zhao, Na Xiang, Fangang Meng, and Ling-ling Lu
- Subjects
Parkinson’s disease ,α-synuclein ,Ephs ,NCK2 ,Synucleinopathies ,Biotechnology ,TP248.13-248.65 ,Biology (General) ,QH301-705.5 ,Biochemistry ,QD415-436 - Abstract
Abstract To investigate physiological function of α-synuclein is important for understanding its pathophysiological mechanism in synucleinopathies including Parkinson’s disease. Employing knockout mice, we found that Snac/α-synuclein deletion induced aberrant projection of olfactory sensory neurons and hyposmia. We identified 9 axon guidance associated differentially expressed proteins using iTRAQ based Liquid Chromatograph Mass Spectrometer. NCK2 is most significantly down-regulated protein among them. We further found that either α-synuclein deletion or NCK2 deficiency induced Eph A4 inactivation. Re-expressing Snac/α-synuclein in its knockout neurons reversed the down-regulation of NCK2, as well as the inactivation of EphA4. Overexpression of Snac/α-synuclein in α-synuclein deleted mice reversed the down-regulation of NCK2 and pEphA4, and improved the olfactory impairment of mice. Correlation analysis showed that there is a significant correlation between the protein level of α-synuclein, NCK2, and pEphA4, respectively. Nonetheless, immunoprecipitation analysis showed that NCK2 was associated with both EphA4 and Rho A, suggesting that NCK2 as a scaffolding protein to modulate Eph A4/Rho A pathway. Moreover, Rho A activity was significantly lower in α-synuclein deficient mice. Thus, α-synuclein regulates olfactory neurons projection through NCK2 dependent EphA4/Rho A pathway. Malfunction of α-synuclein because of deletion may cause aberrant olfactory neurons projection. This extended our knowledge of α-synuclein functions, which may explain why olfaction is usually impaired in some synucleinopathies.
- Published
- 2024
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