Details

Autor(en) / Beteiligte

• de la Rocha-Muñoz, Andrés
• Melgarejo, Elena
• Aragón, Carmen
• López-Corcuera, Beatriz

Titel

Rescue of two trafficking-defective variants of the neuronal glycine transporter GlyT2 associated to hyperekplexia

Ist Teil von

• Neuropharmacology, 2021-05, Vol.189, p.108543-108543, Article 108543

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2021

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. •Two GlyT2 hyperekplexia missense mutations are retained in the ER and show increased binding to calnexin.•The two transporter variants differ in ER export ability and ubiquitination levels.•Calnexin overexpression rescues the membrane arrival and function of the two variants.•Chemical chaperones rescue variant phenotype by decreasing GlyT2/calnexin interaction.•N-arachidonoyl glycine and its derivatives have potential for hyperekplexia therapy.