The couple of netrin-1/α-Synuclein regulates the survival of dopaminergic neurons via α-Synuclein disaggregation
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The abnormal accumulation and aggregation of the misfolded α-synuclein protein is the neuropathological hallmark of all α-synucleinopathies,including Parkinson’s disease. The secreted proteinsknown as netrins (netrin-1, netrin-3, and netrin-4) are relatedto laminin and have a role in the molecular pathway foraxon guidance and cell survival. Interestingly, only netrin-1 is significantlyexpressed in the substantia nigra (SN) of healthy adultbrains and its expression inversely correlates with that of α-synuclein,which prompted us to look into the role of α-synucleinand netrin-1 molecular interaction in the future of dopaminergicneurons. Here, we showed that netrin-1 and α-synuclein directlyinteracted in pre-formed fibrils (PFFs) generation test, realtime binding assay, and co-immunoprecipitation with neurotoxintreated cell lysates. Netrin-1 deficiency appeared to activate thedopaminergic neuronal cell death signal pathway via α-synucleinaggregation and hyperphosphorylation of α-synuclein S129. Takentogether, netrin-1 can be a promising therapeutic molecule inParkinson’s disease.
Abstract
The abnormal accumulation and aggregation of the misfolded α-synuclein protein is the neuropathological hallmark of all α-synucleinopathies,including Parkinson’s disease. The secreted proteinsknown as netrins (netrin-1, netrin-3, and netrin-4) are relatedto laminin and have a role in the molecular pathway foraxon guidance and cell survival. Interestingly, only netrin-1 is significantlyexpressed in the substantia nigra (SN) of healthy adultbrains and its expression inversely correlates with that of α-synuclein,which prompted us to look into the role of α-synucleinand netrin-1 molecular interaction in the future of dopaminergicneurons. Here, we showed that netrin-1 and α-synuclein directlyinteracted in pre-formed fibrils (PFFs) generation test, realtime binding assay, and co-immunoprecipitation with neurotoxintreated cell lysates. Netrin-1 deficiency appeared to activate thedopaminergic neuronal cell death signal pathway via α-synucleinaggregation and hyperphosphorylation of α-synuclein S129. Takentogether, netrin-1 can be a promising therapeutic molecule inParkinson’s disease.
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