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Interplay between APP and glypican-1 (GPC1) processing and α-synuclein (SYN) aggregation in undifferentiated and differentiated human neural progenitor cells (NPC).
Glycobiology 2023 Februrary 16
In Parkinson's disease there is accumulation of α-synuclein (SYN) aggregates in neurons, which is promoted by neuroinflammation. In neural cells, cytokine-induced SYN aggregation is modulated by heparan sulfate (HS) derived from glypican-1 (GPC1) by amyloid precursor protein (APP) and NO-dependent cleavage. We have explored possible interplay between APP, GPC1 and SYN in undifferentiated and differentiated neural progenitor cells (NPC) by modulating APP and GPC1 processing. Effects were monitored by immunofluorescence microscopy and slot immunoblotting using antibodies recognizing APP degradation products, HS released from GPC1, and SYN aggregates (SYNfil). Suppression of HS release from GPC1 by inhibition of β-secretase or by NO-deprivation resulted in no or slight increase in SYNfil aggregation. Stimulation of HS release by ascorbate did not further increase SYNfil staining. Interleukin-6 (IL-6) induced increased APP and GPC1 processing and SYNfil formation, which was reduced when β-secretase was inhibited, and when HS release was impeded by NO-deprivation. Ascorbate restored APP and GPC1 processing but did not affect SYNfil formation. Ascorbate-dependent differentiation of NPC resulted in expression of tyrosine hydroxylase (TH) which co-localized with SYNfil. Suppression of APP processing by inhibition of β-secretase greatly disturbed the differentiation process. IL-6 induced co-clustering of APP-degradation products, TH, HS and SYNfil, which could be reversed by stimulation of HS release from GPC1 by excess ascorbate. We suggest that continuous release of HS from GPC1 moderates SYN aggregation and supports differentiation of NPC to dopaminergic neurons.
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