Rescue by 4-phenylbutyrate of several misfolded creatine transporter-1 variants linked to the creatine transporter deficiency syndrome
El-Kasaby A, Kasture A, Koban F, Hotka M, Asjad HMM, Kubista H, Freissmuth M, Sucic S
Neuropharmacology · 46 citations
Review labels
Neutral facts our review recorded about how this study was done. They describe method, never whether we like the result.
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- Cells or lab samples
- Main outcome
- Mechanisms only
Who paid for it
- Funding
- Independent funding
- Government
- Vienna Science and Technology Fund
- Government
- Austrian Science Fund
- Government
- Austrian Science Fund FWF
- Grants
- Vienna Science and Technology Fund (LS17-026); Vienna Science and Technology Fund (P31255-B27); Austrian Science Fund (P 31255); Austrian Science Fund (P28179); Austrian Science Fund (LS17-026)
Based on 3 listed funder(s).
Publication
- Published
- 2019-03-15 · Neuropharmacology · vol. 161 · p. 107572
- Publisher
- Elsevier BV
- Cited
- 51 citations · more than 85% of similar papers · 2.1× the field average
- References
- 66 works
- Access
- Open access (hybrid journal) · CC-BY-NC-ND
- Research areas
- Muscle metabolism and nutrition · Genetic Neurodegenerative Diseases · Ion channel regulation and function
- Keywords
- Calnexin, Chemical chaperone, Phenylbutyrate, Mutant, Endoplasmic reticulum, Neurotransmitter transporter, Dopamine transporter, Chaperone (clinical), Cell biology, Biology, Transporter, Chemistry, Biochemistry, Unfolded protein response, Endocrinology, Medicine, Gene
- MeSH
- neurons, neurites, cell membrane, endoplasmic reticulum, animals, humans, rats, brain diseases, metabolic, inborn, creatine, phenylbutyrates, calnexin, nerve tissue proteins, mutation, plasma membrane neurotransmitter transport proteins, proteostasis deficiencies, hek293 cells, primary cell culture, x-linked intellectual disability
8 authors
From AT, PK
- Ali El‐KasabyMedical University of Vienna
- Ameya Sanjay KastureUniversity of Vienna; Medical University of Vienna
- Florian KobanMedical University of Vienna
- Matej HoťkaMedical University of Vienna
- Hafiz Muhammad Mazhar AsjadForman Christian College; Medical University of Vienna
- Helmut KubistaMedical University of Vienna
Abstract
Diseases arising from misfolding of SLC6 transporters have been reported over recent years, e.g. folding-deficient mutants of the dopamine transporter and of the glycine transporter-2 cause infantile/juvenile Parkinsonism dystonia and hyperekplexia, respectively. Mutations in the coding sequence of the human creatine transporter-1 (hCRT-1/SLC6A8) gene result in a creatine transporter deficiency syndrome, which varies in its clinical manifestation from epilepsy, mental retardation, autism, development delay and motor dysfunction to gastrointestinal symptoms. Some of the mutations in hCRT-1 occur at residues, which are highly conserved across the SLC6 family. Here, we examined 16 clinically relevant hCRT-1 variants to verify the conjecture that they were misfolded and that this folding defect was amenable to correction. Confocal microscopy imaging revealed that the heterologously expressed YFP-tagged mutant CRTs were trapped in the endoplasmic reticulum (ER), co-localised with the ER-resident chaperone calnexin. In contrast, the wild type hCRT-1 reached the plasma membrane. Preincubation of transiently transfected HEK293 cells with the chemical chaperone 4-phenylbutyrate (4-PBA) restored ER export and surface expression of as well as substrate uptake by several folding-deficient CRT-1 mutants. A representative mutant (hCRT-1-P544L) was expressed in rat primary hippocampal neurons to verify pharmacochaperoning in a target cell: 4-PBA promoted the delivery of hCRT-1-P544L to the neurite extensions. These observations show that several folding-deficient hCRT-1 mutants can be rescued. This proof-of-principle justifies the search for additional pharmacochaperones to restore folding of 4PBA-unresponsive hCRT-1 mutants. Finally, 4-PBA is an approved drug in paediatric use: this provides a rationale for translating the current insights into clinical trials. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC-ND).
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