Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells
Cheng, Fang LU ; Fransson, Lars Åke LU and Mani, Katrin LU
(2022)
In Glycobiology
32(4).
p.333-342
- Abstract
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... (More)
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.
(Less)
- author
- Cheng, Fang
LU
; Fransson, Lars Åke
LU
and Mani, Katrin
LU
- organization
- publishing date
- 2022-04-01
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- glypican-1, heparan sulfate, nitric oxide, Parkinson's disease, α-synuclein
- in
- Glycobiology
- volume
- 32
- issue
- 4
- pages
- 333 - 342
- publisher
- Oxford University Press
- external identifiers
-
- pmid:34939110
- scopus:85128160655
- ISSN
- 0959-6658
- DOI
- 10.1093/glycob/cwab126
- language
- English
- LU publication?
- yes
- id
- 2652c925-5975-4e30-bc08-d17034bfcf85
- date added to LUP
- 2022-07-01 12:03:52
- date last changed
- 2024-06-13 17:52:15
@article{2652c925-5975-4e30-bc08-d17034bfcf85,
abstract = {{<p>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. </p>}},
author = {{Cheng, Fang and Fransson, Lars Åke and Mani, Katrin}},
issn = {{0959-6658}},
keywords = {{glypican-1; heparan sulfate; nitric oxide; Parkinson's disease; α-synuclein}},
language = {{eng}},
month = {{04}},
number = {{4}},
pages = {{333--342}},
publisher = {{Oxford University Press}},
series = {{Glycobiology}},
title = {{Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells}},
url = {{http://dx.doi.org/10.1093/glycob/cwab126}},
doi = {{10.1093/glycob/cwab126}},
volume = {{32}},
year = {{2022}},
}