Overexpression of alpha-Synuclein Reorganises Growth Factor Profile of Human Astrocytes

Abstract

Misfolding and accumulation of aberrant alpha-synuclein in the brain is associated with the distinct class of neurodegenerative diseases known as alpha-synucleinopathies, which include Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Pathological changes in astrocytes contribute to all neurological disorders, and astrocytes are reported to possess alpha-synuclein inclusions in the context of alpha-synucleinopathies. Astrocytes are known to express and secrete numerous growth factors, which are fundamental for neuroprotection, synaptic connectivity and brain metabolism; changes in growth factor secretion may contribute to pathobiology of neurological disorders. Here we analysed the effect of alpha-synuclein overexpression in cultured human astrocytes on growth factor expression and release. For this purpose, the intracellular and secreted levels of 33 growth factors (GFs) and 8 growth factor receptors (GFRs) were analysed in cultured human astrocytes by chemiluminescence-based western/dot blot. Overexpression of human alpha-synuclein in cultured foetal human astrocytes significantly changes the profile of GF production and secretion. We found that human astrocytes express and secrete FGF2, FGF6, EGF, IGF1, AREG, IGFBP2, IGFBP4, VEGFD, PDGFs, KITLG, PGF, TGFB3 and NTF4. Overexpression of human alpha-synuclein significantly modified the profile of GF production and secretion, with particularly strong changes in EGF, PDGF, VEGF and their receptors as well as in IGF-related proteins. Bioinformatics analysis revealed possible interactions between alpha-synuclein and EGFR and GDNF, as well as with three GF receptors, EGFR, CSF1R and PDGFRB.