Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability

Abstract

Hevin is a secreted extracellular matrix protein that is encoded by SPARCL1 gene. Recent studies show that Hevin plays an important role in regulating synaptogenesis and synaptic plasticity. Mutations in SPARCL1 gene increase the risk of autism spectrum disorder (ASD). However, the molecular basis of how mutations in SPARCL1 increase the risk of ASD has not been fully understood. In this study, we show that one of SPARCL1 mutations associated with ASD impairs normal Hevin secretion. We identified Hevin mutants lacking the EF-hand motif through analyzing ASD-related mice with vulnerable spliceosome functions. Hevin deletion mutants accumulate in the ER, leading to the activation of unfolded protein responses. We also found that a single amino acid substitution of Trp647 with Arg in the EF-hand motif associated with a familial case of ASD causes a similar phenotype with the EF-hand deletion mutant. Importantly, molecular dynamics (MD) simulation revealed that this single amino acid substitution triggers exposure of hydrophobic amino acid to the surface, increasing the binding of Hevin with a molecular chaperon, BIP. Taken together, these data suggest that the integrity of EF-hand motif in Hevin is crucial for proper folding and ASD-related mutation impairs an export of Hevin from the endoplasmic reticulum (ER). Our data provide a novel mechanism linking a point mutation in SPARCL1 gene to the molecular and cellular characteristics involved in ASD.

Autism: genetics, environmental stressors, maternal immune activation, and the male bias in autism

“…For example, the secreted protein acidic and rich in cysteine-like protein 1 gene (Sparcl1) or high endothelial venule protein (Hevin) gene encodes an extracellular matrix protein that plays an important role in regulating synaptogenesis and synaptic plasticity. Mutation of this gene results in the production of a misfolded HEVIN protein which cannot be transported out of the endoplasmic and has been associated with an increased risk of ASD [35]. A similar mutation has been noted in the Neuroligin3 (NLGN3) gene which also encodes extracellular matrix proteins.…”

Loss of maturity and homeostatic functions in Tuberous Sclerosis Complex-derived astrocytes

“…Other targets that we examined such as SPARCL1 are not directly involved in phagocytosis, but perform an associative role with synapses and their formation. Their downregulation is known to cause impairment of synapse formation (Singh et al, 2016), plasticity (Jones et al, 2011) and has been associated with ER stress in autism spectrum disorder (Taketomi et al, 2022). Therefore, they could pose an interesting future target in respects to epileptic network formation in TSC.…”

Proteina matrizelularren inplikazioa gaixotasun neuropsikiatrikoetan, hevin proteinan zentratuta

“…EF-besoa: His611-Phe637 aminoazidoak saguetan) eta kaltzioaren menpeko eta kontzentrazio txikiko 8 afinitatetarekin I eta V kolagenoei lotzen dela ikusi izan da orain dela gutxi, SPARC proteinak kolagenoekin duen elkarrekintza antzeko batekin [37,38,41]. EF-besoak beharrezkoak dira hevin proteina zuzen tolesteko eta bere garraiorako erretikulu endoplasmatikotik zelulaz kanpoko matrizeraino [42]. Azkenik, duela gutxi aurkitu da hevinaren C-terminalak (FS-EC tandem domeinuak barne) elkarrekintzan diharduela kaltzion izeneko (calcyon, ingelesez) neuronentzako espezifikoa den proteina besikular baten N-terminalarekin, burmuineko lesioen ondoren ematen den sinapsien berreskurapenean parte hartuz [43].…”

“…Konexio talamokortikalek ere alterazioak erakusten dituzte AEGn, hipotesi hau bermatuz [99]. Era berean, orain dela gutxiko lan batek erakusten du SPARCL1 genearen mutazioetako batek, EF-besoaren motiboa falta duen hevinentzat kodifikatzen duenak, hevina erretikulu endoplasmatikoan metatzea eragiten duela [42]. Horrek, hevinen jariaketa kaltetzen du eta txarto tolestutako proteinen erantzunak aktibatzea eragiten du [42].…”

“…Era berean, orain dela gutxiko lan batek erakusten du SPARCL1 genearen mutazioetako batek, EF-besoaren motiboa falta duen hevinentzat kodifikatzen duenak, hevina erretikulu endoplasmatikoan metatzea eragiten duela [42]. Horrek, hevinen jariaketa kaltetzen du eta txarto tolestutako proteinen erantzunak aktibatzea eragiten du [42]. Hevinen alterazioak erakusten dituen beste neurogarapenako gaitz bat Fragile X sindromea da, non hevin proteinaren adierazpenaren erregulazio okerra deskribatu da, garunatal espezifikotasunarekin [100].…”