Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia
| Autor: | Andrés de la Rocha-Muñoz, Elena Melgarejo, Beatriz López-Corcuera, Carmen Aragón |
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| Přispěvatelé: | Ministerio de Economía y Competitividad (España), Fundación Ramón Areces, Banco Santander |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Calnexin Mutation Missense Glycine Transport Arachidonic Acids Sudden death Glycine transporter 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Glycine Plasma Membrane Transport Proteins Chlorocebus aethiops medicine Animals Hyperekplexia Rats Wistar Glycine receptor Cells Cultured Pharmacology Neurons biology Chemistry Endoplasmic reticulum Genetic Variation Cell biology Rats Protein Transport Chemical chaperone 030104 developmental biology Chaperone (protein) COS Cells biology.protein Female Hyperekplexia Mutation medicine.symptom 030217 neurology & neurosurgery |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Hyperekplexia is a rare sensorimotor syndrome characterized by pathological startle reflex in response to unexpected trivial stimuli for which there is no specific treatment. Neonates suffer from hypertonia and are at high risk of sudden death due to apnea episodes. Mutations in the human SLC6A5 gene encoding the neuronal glycine transporter GlyT2 may disrupt the inhibitory glycinergic neurotransmission and cause a presynaptic form of the disease. The phenotype of missense mutations giving rise to protein misfolding but maintaining residual activity could be rescued by facilitating folding or intracellular trafficking. In this report, we characterized the trafficking properties of two mutants associated with hyperekplexia (A277T and Y707C, rat numbering). Transporter molecules were partially retained in the endoplasmic reticulum showing increased interaction with the endoplasmic reticulum chaperone calnexin. One transporter variant had export difficulties and increased ubiquitination levels, suggestive of enhanced endoplasmic reticulum-associated degradation. However, the two mutant transporters were amenable to correction by calnexin overexpression. Within the search for compounds capable of rescuing mutant phenotypes, we found that the arachidonic acid derivative N-arachidonoyl glycine can rescue the trafficking defects of the two variants in heterologous cells and rat brain cortical neurons. N-arachidonoyl glycine improves the endoplasmic reticulum output by reducing the interaction transporter/calnexin, increasing membrane expression and improving transport activity in a comparable way as the well-established chemical chaperone 4-phenyl-butyrate. This work identifies N-arachidonoyl glycine as a promising compound with potential for hyperekplexia therapy. Spanish ‘Ministerio de Economía y Competitividad’, grant number SAF2017-84235-R (AEI/ FEDER, EU) to B.L.-C. and by institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO |
| Databáze: | OpenAIRE |
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