Abstract

Synucleinopathies such as Parkinsons disease, dementia with Lewy bodies and multiple system atrophy are characteristic for -synuclein aggregates in neurons or glia, and are always manifested olfaction deficits at their primary onsets. It remains elusive why aggregation of -synuclein predominantly affect the olfactory system. Employing the knockout mice, we investigate the physiological function of -synuclein in olfactory system. We found that deletion of -synuclein primarily interferes the projection of olfactory sensory neurons. iTRAQ based LC-MS identified that 188 proteins are differentially expressed, including 9 that were associated with axon guidance. Among them, NCK2 is most significantly down-regulated, which was indicated to be involved a PPI network of 21 proteins, including 11 players of the Ephrin receptor signaling pathway. Either -synuclein deletion or NCK2 deficiency can inactivate Eph A4 receptor. Re-expressing -synuclein in the -synuclein knockout neurons reverse the NCK2, as well as the phosphorylated Eph A4 (the activated Eph A4). Thus, -synuclein regulates axon guidance through NCK2-Eph A4 signaling pathway. Malfunction of -synuclein, whether because of deletion or aggregation, may cause aberrant olfactory neurons projection and subsequent olfaction deficits. This extended our knowledge of effects of -synuclein in olfactory system, which may explain why olfaction is usually impaired in some synucleinopathy related disorders such as Parkinsons disease.