Journal article
Glucosamine amends CNS pathology in mucopolysaccharidosis IIIC mouse expressing misfolded HGSNAT
- Abstract:
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, 8.7MB, Terms of use)
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- Publisher copy:
- 10.1084/jem.20211860
Authors
- Publisher:
- Rockefeller University Press
- Journal:
- Journal of Experimental Medicine More from this journal
- Volume:
- 219
- Issue:
- 8
- Article number:
- e20211860
- Publication date:
- 2022-06-15
- Acceptance date:
- 2022-05-02
- DOI:
- EISSN:
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1540-9538
- ISSN:
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0022-1007
- Language:
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English
- Keywords:
- Pubs id:
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1260111
- Local pid:
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pubs:1260111
- Deposit date:
-
2022-05-19
Terms of use
- Copyright holder:
- Pan et al.
- Copyright date:
- 2022
- Rights statement:
- © 2022 Pan et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
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