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Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells
In Parkinson’s disease (PD), there is accumulation of α-synuclein (SYN) aggregates in neurons, which is promoted by neuroinflammation. The cytokines TNF-α, IL-1β and IL-6 induce accumulation of degradation products of the amyloid precursor protein (APP) combined with heparan sulfate (HS) chains rele...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970428/ https://www.ncbi.nlm.nih.gov/pubmed/34939110 http://dx.doi.org/10.1093/glycob/cwab126 |
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author | Cheng, Fang Fransson, Lars-Åke Mani, Katrin |
author_facet | Cheng, Fang Fransson, Lars-Åke Mani, Katrin |
author_sort | Cheng, Fang |
collection | PubMed |
description | In Parkinson’s disease (PD), there is accumulation of α-synuclein (SYN) aggregates in neurons, which is promoted by neuroinflammation. The cytokines TNF-α, IL-1β and IL-6 induce accumulation of degradation products of the amyloid precursor protein (APP) combined with heparan sulfate (HS) chains released from glypican-1 (Gpc-1) by NO-dependent cleavage. We have investigated the effects of the cytokines and HS on SYN aggregation and secretion in dividing human neuroblastoma (SH-SY5Y) and inducible neural progenitor cells (NPC) by using immunofluorescence microscopy, vesicle isolation and slot blotting with antibodies recognizing SYN monomers and aggregates, Gpc-1, the released HS, endosomes, and autophagosomes. In SH-SY5Y cells, the capacity to release HS was fully utilized, while NPC displayed dormant capacity. TNF-α induced increased formation of SYN aggregates and clustering of HS in SH-SY5Y cells. When the supply of NO was simultaneously increased, SYN and HS accumulation disappeared. When NO formation was inhibited, SYN and HS aggregation also disappeared, but there was now a 4-fold increase in SYN secretion. In NPC, IL-6 induced increased aggregation of SYN and stimulated HS release from Gpc-1. Both SYN and HS co-localized with autophagosome marker. When HS-deficient Gpc-1 was simultaneously generated, by using a cyanobacterial neurotoxin, accumulation diminished and there was massive secretion of SYN. We suggest that the cytokines increase APP processing, which initiates NO-dependent release of HS from Gpc-1. The APP degradation products also trigger SYN aggregation. As HS can inhibit APP processing, HS- or NO-deficiency may result in autophagosomal dysfunction and both APP degradation products and SYN are secreted. |
format | Online Article Text |
id | pubmed-8970428 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-89704282022-04-01 Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells Cheng, Fang Fransson, Lars-Åke Mani, Katrin Glycobiology Original Article In Parkinson’s disease (PD), there is accumulation of α-synuclein (SYN) aggregates in neurons, which is promoted by neuroinflammation. The cytokines TNF-α, IL-1β and IL-6 induce accumulation of degradation products of the amyloid precursor protein (APP) combined with heparan sulfate (HS) chains released from glypican-1 (Gpc-1) by NO-dependent cleavage. We have investigated the effects of the cytokines and HS on SYN aggregation and secretion in dividing human neuroblastoma (SH-SY5Y) and inducible neural progenitor cells (NPC) by using immunofluorescence microscopy, vesicle isolation and slot blotting with antibodies recognizing SYN monomers and aggregates, Gpc-1, the released HS, endosomes, and autophagosomes. In SH-SY5Y cells, the capacity to release HS was fully utilized, while NPC displayed dormant capacity. TNF-α induced increased formation of SYN aggregates and clustering of HS in SH-SY5Y cells. When the supply of NO was simultaneously increased, SYN and HS accumulation disappeared. When NO formation was inhibited, SYN and HS aggregation also disappeared, but there was now a 4-fold increase in SYN secretion. In NPC, IL-6 induced increased aggregation of SYN and stimulated HS release from Gpc-1. Both SYN and HS co-localized with autophagosome marker. When HS-deficient Gpc-1 was simultaneously generated, by using a cyanobacterial neurotoxin, accumulation diminished and there was massive secretion of SYN. We suggest that the cytokines increase APP processing, which initiates NO-dependent release of HS from Gpc-1. The APP degradation products also trigger SYN aggregation. As HS can inhibit APP processing, HS- or NO-deficiency may result in autophagosomal dysfunction and both APP degradation products and SYN are secreted. Oxford University Press 2021-12-07 /pmc/articles/PMC8970428/ /pubmed/34939110 http://dx.doi.org/10.1093/glycob/cwab126 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Cheng, Fang Fransson, Lars-Åke Mani, Katrin Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells |
title | Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells |
title_full | Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells |
title_fullStr | Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells |
title_full_unstemmed | Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells |
title_short | Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells |
title_sort | complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970428/ https://www.ncbi.nlm.nih.gov/pubmed/34939110 http://dx.doi.org/10.1093/glycob/cwab126 |
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