Synucleinopathies such as Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy are characteristic for α -synuclein aggregates in neurons or glia, and are always manifested olfaction deficits at their primary onsets. It remains elusive why aggregation of α -synuclein predominantly affect the olfactory system. Employing the knockout mice, we investigate the physiological function of α-synuclein in olfactory system. We found that deletion of α-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 α-synuclein deletion or NCK2 deficiency can inactivate Eph A4 receptor. Re-expressing α-synuclein in the α-synuclein knockout neurons reverse the NCK2, as well as the phosphorylated Eph A4 (the activated Eph A4). Thus, α-synuclein regulates axon guidance through NCK2-Eph A4 signaling pathway. Malfunction of α-synuclein, whether because of deletion or aggregation, may cause aberrant olfactory neurons projection and subsequent olfaction deficits. This extended our knowledge of effects of α-synuclein in olfactory system, which may explain why olfaction is usually impaired in some synucleinopathy related disorders such as Parkinson’s disease.

SNCA Deletion Induced Aberrant Projection of Olfactory Sensory Neurons via NCK2-EphA4 Pathway