Glucosamine amends CNS pathology in mucopolysaccharidosis IIIC mouse expressing misfolded HGSNAT.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 08 2022
01 08 2022
Historique:
received:
08
09
2021
revised:
26
02
2022
accepted:
02
05
2022
entrez:
15
6
2022
pubmed:
16
6
2022
medline:
18
6
2022
Statut:
ppublish
Résumé
The majority of mucopolysaccharidosis IIIC (MPS IIIC) patients have missense variants causing misfolding of heparan sulfate acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT), which are potentially treatable with pharmacological chaperones. To test this approach, we generated a novel HgsnatP304L mouse model expressing misfolded HGSNAT Pro304Leu variant. HgsnatP304L mice present deficits in short-term and working/spatial memory 2-4 mo earlier than previously described constitutive knockout Hgsnat-Geo mice. HgsnatP304L mice also show augmented severity of neuroimmune response, synaptic deficits, and neuronal storage of misfolded proteins and gangliosides compared with Hgsnat-Geo mice. Expression of misfolded human Pro311Leu HGSNAT protein in cultured hippocampal Hgsnat-Geo neurons further reduced levels of synaptic proteins. Memory deficits and majority of brain pathology were rescued in mice receiving HGSNAT chaperone, glucosamine. Our data for the first time demonstrate dominant-negative effects of misfolded HGSNAT Pro304Leu variant and show that they are treatable by oral administration of glucosamine. This suggests that patients affected with mutations preventing normal folding of the enzyme can benefit from chaperone therapy.
Identifiants
pubmed: 35704026
pii: 213285
doi: 10.1084/jem.20211860
pmc: PMC9204472
pii:
doi:
Substances chimiques
Heparitin Sulfate
9050-30-0
Acetyltransferases
EC 2.3.1.-
HGSNAT protein, human
EC 2.3.1.78
Glucosamine
N08U5BOQ1K
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : PJT-156345
Pays : Canada
Organisme : Elisa Linton Sanfilippo Research Laboratory
Organisme : JLK Foundation
Organisme : Sanfilippo Children's Research Foundation
Organisme : Mizutani Foundation
Organisme : Jonah's Just Began Foundation
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wolfson Royal Society
Organisme : Canadian MPS Society
Organisme : Canadian Glycomics Network
Informations de copyright
© 2022 Pan et al.
Références
JIMD Rep. 2015 Oct 23;:
pubmed: 26493749
N Engl J Med. 2016 Aug 11;375(6):545-55
pubmed: 27509102
J Biol Chem. 2007 Mar 23;282(12):9150-61
pubmed: 17237499
Glycobiology. 1999 Dec;9(12):1389-96
pubmed: 10561464
Mol Metab. 2018 Jun;12:76-88
pubmed: 29735266
Biochim Biophys Acta Mol Cell Res. 2021 Oct;1868(11):119113
pubmed: 34329663
Ann Clin Transl Neurol. 2016 Feb 02;3(3):200-15
pubmed: 27042680
Hum Mutat. 2019 Aug;40(8):1084-1100
pubmed: 31228227
Nat Med. 1999 Jan;5(1):112-5
pubmed: 9883849
JCI Insight. 2021 Aug 9;6(15):
pubmed: 34156977
Curr Drug Targets. 2016;17(11):1275-81
pubmed: 26648081
Eur J Pediatr. 1979 Apr 3;130(4):251-8
pubmed: 108106
PLoS One. 2015 Aug 19;10(8):e0135873
pubmed: 26287674
J Clin Med. 2020 Jan 27;9(2):
pubmed: 32012694
Mol Genet Metab. 2008 Feb;93(2):104-11
pubmed: 18024218
J Neurol. 2004 Apr;251(4):479-81
pubmed: 15083297
Anal Biochem. 2004 Aug 15;331(2):275-82
pubmed: 15265733
Brain. 2015 Feb;138(Pt 2):336-55
pubmed: 25567323
J Physiol. 2010 Jun 15;588(Pt 12):2091-107
pubmed: 20403974
J Inherit Metab Dis. 2004;27(3):385-410
pubmed: 15190196
Autophagy. 2018;14(8):1419-1434
pubmed: 29916295
J Med Chem. 2013 Apr 11;56(7):2705-25
pubmed: 23363020
J Clin Invest. 2007 Jun;117(6):1585-94
pubmed: 17549255
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15428-33
pubmed: 12434014
PLoS One. 2009 Aug 06;4(8):e6529
pubmed: 19657394
Science. 1999 Dec 3;286(5446):1882-8
pubmed: 10583943
N Engl J Med. 2001 Jul 5;345(1):25-32
pubmed: 11439944
J Biol Chem. 2004 Apr 2;279(14):13478-87
pubmed: 14724290
Cell Death Differ. 2007 Mar;14(3):511-23
pubmed: 16888648
Mol Ther. 2014 Nov;22(11):2004-12
pubmed: 25052852
FASEB J. 2017 Aug;31(8):3467-3483
pubmed: 28442549
Rheum Dis Clin North Am. 2011 Feb;37(1):103-18
pubmed: 21220090
Exp Diabetes Res. 2012;2012:187018
pubmed: 22474416
EMBO Mol Med. 2009 Aug;1(5):268-79
pubmed: 20049730
Nucleic Acids Res. 2009 Jan;37(1):1-13
pubmed: 19033363
Trends Cell Biol. 1992 Aug;2(8):227-31
pubmed: 14731479
Development. 2010 Oct;137(20):3383-91
pubmed: 20826529
Behav Brain Res. 2012 Jul 1;232(2):335-47
pubmed: 22490364
EMBO Mol Med. 2020 Mar 6;12(3):e11185
pubmed: 32057196
J Inherit Metab Dis. 2008 Apr;31(2):240-52
pubmed: 18392742
Hum Mutat. 2009 Jun;30(6):918-25
pubmed: 19479962
Nature. 2010 Nov 11;468(7321):263-9
pubmed: 21068835
J Clin Med. 2020 Feb 01;9(2):
pubmed: 32024172
Cancer Res. 1994 Mar 15;54(6):1511-6
pubmed: 8137257
PLoS One. 2009 Oct 13;4(10):e7434
pubmed: 19823584
Cogn Process. 2012 May;13(2):93-110
pubmed: 22160349
Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14505-10
pubmed: 10588735
Orphanet J Rare Dis. 2014 Dec 10;9:180
pubmed: 25491247
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15912-7
pubmed: 14676316
Hum Mutat. 2010 Jul;31(7):E1574-86
pubmed: 20583299
Behav Brain Res. 1988 Nov 1;31(1):47-59
pubmed: 3228475
Biomed Biochim Acta. 1985;44(4):611-22
pubmed: 4026816
PLoS One. 2008 May 28;3(5):e2296
pubmed: 18509511
Nat Commun. 2021 Jun 16;12(1):3653
pubmed: 34135323
Mol Ther. 2020 Apr 8;28(4):1167-1176
pubmed: 32087148
Curr Signal Transduct Ther. 2010 Jan;5(1):49-59
pubmed: 22308107
Eur J Biochem. 2000 Jul;267(13):4179-86
pubmed: 10866822
Nat Rev Mol Cell Biol. 2003 Mar;4(3):181-91
pubmed: 12612637