Extracellular α‐synuclein impairs sphingosine 1‐phosphate receptor type 3 (S1PR3)‐regulated lysosomal delivery of cathepsin D in HeLa cells

Abstract

Abstractα‐Synuclein (α‐Syn)‐positive intracellular fibrillar protein deposits, known as Lewy bodies, are thought to be involved in the pathogenesis of Parkinson's disease (PD). Although recent lines of evidence suggested that extracellular α‐Syn secreted from pathogenic neurons contributes to the propagation of PD pathology, the precise mechanism of action remains unclear. We have reported that extracellular α‐Syn caused sphingosine 1‐phosphate (S1P) receptor type 1 (S1PR1) uncoupled from Gi and inhibited downstream G‐protein signaling in SH‐SY5Y cells, although its patho/physiological role remains to be clarified. Here we show that extracellular α‐Syn caused S1P receptor type 3 (S1PR3) uncoupled from G protein in HeLa cells. Further studies indicated that α‐Syn treatment reduced cathepsin D activity while enhancing the secretion of immature pro‐cathepsin D into cell culture medium, suggesting that lysosomal delivery of cathepsin D was disturbed. Actually, extracellular α‐Syn attenuated the retrograde trafficking of insulin‐like growth factor‐II/mannose 6‐phosphate (IGF‐II/M6P) receptor, which is under the regulation of S1PR3. These findings shed light on the understanding of dissemination of the PD pathology, that is, the mechanism underlying how extracellular α‐Syn secreted from pathogenic cells causes lysosomal dysfunction of the neighboring healthy cells, leading to propagation of the disease.