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 citas
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Cómo se estudió
- Diseño
- Estudio in vitro o de mecanismos (clasificado por nuestro filtro de IA)
- Estudiado en
- Células o muestras de laboratorio
- Resultado principal
- Solo mecanismos
Quién lo pagó
- Financiación
- Financiación independiente
- Gobierno
- Vienna Science and Technology Fund
- Gobierno
- Austrian Science Fund
- Gobierno
- Austrian Science Fund FWF
- Subvenciones
- 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)
Según 3 financiadores declarados.
Publicación
- Publicado
- 2019-03-15 · Neuropharmacology · vol. 161 · pág. 107572
- Editorial
- Elsevier BV
- Citado
- 51 citas · más que el 85% de estudios similares · 2.1× el promedio de su campo
- Referencias
- 66 trabajos
- Acceso
- Acceso abierto (revista híbrida) · CC-BY-NC-ND
- Áreas de investigación
- Muscle metabolism and nutrition · Genetic Neurodegenerative Diseases · Ion channel regulation and function
- Palabras clave
- 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 autores
- Ali El‐Kasaby🇦🇹Medical University of Vienna
- Ameya Sanjay Kasture🇦🇹University of Vienna; Medical University of Vienna
- Florian Koban🇦🇹Medical University of Vienna
- Matej Hoťka🇦🇹Medical University of Vienna
- Hafiz Muhammad Mazhar Asjad🇵🇰🇦🇹Forman Christian College; Medical University of Vienna
- Helmut Kubista🇦🇹Medical University of Vienna
- Michael Freissmuth🇦🇹Medical University of Vienna
- Sonja Sučić🇦🇹 · autor de correspondenciaMedical University of Vienna
Resumen
El texto original del estudio, en el idioma en que se publicó.
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'.
Resumen vía Europe PMC. Los derechos de autor siguen siendo de los autores o la editorial (CC BY-NC-ND).
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