Interplay between APP and glypican-1 processing and α-synuclein aggregation in undifferentiated and differentiated human neural progenitor cells

被引:4
作者
Cheng, Fang [1 ]
Fransson, Lars-ake [1 ]
Mani, Katrin [1 ]
机构
[1] Lund Univ, Biomed Ctr A13, Dept Expt Med Sci, Div Neurosci,Glycobiol Grp, SE-22184 Lund, Sweden
关键词
amyloid precursor protein; glypican-1; heparan sulfate; Parkinson's disease; alpha-synuclein; AMYLOID PRECURSOR PROTEIN; HEPARAN-SULFATE; ALZHEIMERS-DISEASE; INDUCED RELEASE; BETA; DEGRADATION; ACCUMULATION; SUPPRESSION; PEPTIDE; NITRITE;
D O I
10.1093/glycob/cwad013
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In Parkinson's disease, there is an accumulation of alpha-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 nitric oxide (NO)-dependent cleavage. We have explored possible interplay between APP, GPC1, and SYN in undifferentiated and differentiated neural progenitor cells (NPCs) 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 (filamentous SYN [SYNfil]). Suppression of HS release from GPC1 by inhibition of beta-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 beta-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 the expression of tyrosine hydroxylase (TH) which colocalized with SYNfil. Suppression of APP processing by inhibition of beta-secretase greatly disturbed the differentiation process. IL-6 induced coclustering 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.
引用
收藏
页码:325 / 341
页数:17
相关论文
共 39 条
[1]   Nuclear Translocation Uncovers the Amyloid Peptide Aβ42 as a Regulator of Gene Transcription [J].
Barucker, Christian ;
Harmeier, Anja ;
Weiske, Joerg ;
Fauler, Beatrix ;
Albring, Kai Frederik ;
Prokop, Stefan ;
Hildebrand, Peter ;
Lurz, Rudi ;
Heppner, Frank L. ;
Huber, Otmar ;
Multhaup, Gerhard .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (29) :20182-20191
[2]   The Function of α-Synuclein [J].
Bendor, Jacob T. ;
Logan, Todd P. ;
Edwards, Robert H. .
NEURON, 2013, 79 (06) :1044-1066
[3]   The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes [J].
Benilova, Iryna ;
Karran, Eric ;
De Strooper, Bart .
NATURE NEUROSCIENCE, 2012, 15 (03) :349-357
[4]   Neuroinflammation in Alzheimer's disease: Current evidence and future directions [J].
Calsolaro, Valeria ;
Edison, Paul .
ALZHEIMERS & DEMENTIA, 2016, 12 (06) :719-732
[5]   Xanthine oxidoreductase-catalyzed reduction of nitrite to nitric oxide: Insights regarding where, when and how [J].
Cantu-Medellin, Nadiezhda ;
Kelley, Eric E. .
NITRIC OXIDE-BIOLOGY AND CHEMISTRY, 2013, 34 :19-26
[6]   The amyloid precursor protein (APP) of Alzheimer disease and its paralog, APLP2, modulate the Cu/Zn-nitric oxide-catalyzed degradation of glypican-1 heparan sulfate in vivo [J].
Cappai, R ;
Cheng, F ;
Ciccotosto, GD ;
Needham, BE ;
Masters, CL ;
Multhaup, G ;
Fransson, LÅ ;
Mani, K .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (14) :13913-13920
[7]   BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice [J].
Chatila, Zena K. ;
Kim, Eunhee ;
Berle, Clara ;
Bylykbashi, Enjana ;
Rompala, Alexander ;
Oram, Mary K. ;
Gupta, Drew ;
Kwak, Sang Su ;
Kim, Young Hye ;
Kim, Doo Yeon ;
Choi, Se Hoon ;
Tanzi, Rudolph E. .
ENEURO, 2018, 5 (04)
[8]   Nitric oxide-dependent processing of heparan sulfate in recycling S-nitrosylated glypican-1 takes place in caveolin-1-containing endosomes [J].
Cheng, F ;
Mani, K ;
van den Born, J ;
Ding, K ;
Belting, M ;
Fransson, LÅ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (46) :44431-44439
[9]   Complex modulation of cytokine-induced α-synuclein aggregation by glypican-1-derived heparan sulfate in neural cells [J].
Cheng, Fang ;
Fransson, Lars-Ake ;
Mani, Katrin .
GLYCOBIOLOGY, 2022, 32 (04) :333-342
[10]   Reversal of apolipoprotein E4-dependent or chemical-induced accumulation of APP degradation products by vitamin C-induced release of heparan sulfate from glypican-1 [J].
Cheng, Fang ;
Fransson, Lars-Ake ;
Mani, Katrin .
GLYCOBIOLOGY, 2021, 31 (07) :800-811