Summary: A study reveals that a genetic mutation linked to autism increases splicing errors and induces endoplasmic reticulum stress by activating the unfolded protein response.
Source: University of Tsukuba
Anyone who has ever been stuck in a traffic jam can attest to the disruption it causes to your day. Now, Japanese researchers have discovered that a mutation associated with autism can cause a traffic jam of unfolded proteins that disrupts normal brain function.
In a study recently published in Scientific reportsresearchers from the University of Tsukuba reveal that a mutation in an autism-associated protein called Hevin impairs its normal processing and secretion.
Many genetic mutations associated with autism spectrum disorders have been identified to date, including some inherited mutations. However, in most cases, the functional effects of these mutations have not been determined.
“We have previously found that mutation of the Usp15 gene, which is closely associated with autism, increases the likelihood of splicing errors and induces endoplasmic reticulum stress by activating the unfolded protein response,” explains Professor Fuminori Tsuruta . “However, it’s still unclear how it causes these effects.”
To address this issue, the researchers searched for autism-associated variants that exhibited abnormal splicing in the absence of Usp15 in mouse brains and found that the end of the transcript encoding a protein called Hevin tended to to be lacking. Curiously, a mutation in the same part of Hevin, known as the EF hand pattern, has been linked to a familial case of autism.
“Analysis of the Hevin deletion mutant and the Hevin variant with a single point mutation showed that both mutants accumulate in the endoplasmic reticulum, leading to activation of the unfolded protein response,” says Professor Tsuruta.
Importantly, structural modeling of the Hevin mutation associated with familial autism has shown that this single amino acid substitution triggers the exposure of a hydrophobic amino acid on the surface. This change is likely to cause structural instability and interfere with export from the endoplasmic reticulum.
“Taken together, our results suggest that the integrity of the EF hand pattern in Hevin is crucial for correct folding, and that autism-related mutations impede the export of Hevin from the endoplasmic reticulum,” says Professor Tsuruta .
Given that several other autism-related mutations have also been shown to promote the accumulation of synaptic proteins in the endoplasmic reticulum, it is possible that the resulting impairment of neuronal function contributes to the pathogenesis of the disease. ‘autism.
Future studies could help reveal how the endoplasmic reticulum stress response affects neural circuitry and brain homeostasis and clarify the link with the development of autism.
About this genetics and autism research news
Author: Press office
Source: University of Tsukuba
Contact: Press Office – University of Tsukuba
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Original research: Free access.
“Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability” by Takumi Taketomi et al. Scientific reports
Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability
Hevin is a secreted extracellular matrix protein that is encoded by the SPARCL1 embarrassed. Recent studies have shown that Hevin plays an important role in the regulation of synaptogenesis and synaptic plasticity. Mutations in the SPARCL1 gene increases 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 the SPARCL1 ASD-associated mutations impair normal Hevin secretion.
We identified Hevin mutants lacking the EF-hand motif by analyzing TSA-related mice with vulnerable spliceosome functions. Hevin deletion mutants accumulate in the endoplasmic reticulum (ER), leading to activation of unfolded protein responses.
We also found that a single amino acid substitution of Trp647 with Arg in the EF-main motif associated with a familial case of ASD causes a similar phenotype in the EF-main deletion mutant. Importantly, molecular dynamics (MD) simulation revealed that this single amino acid substitution triggers the exposure of a hydrophobic amino acid on the surface, increasing Hevin’s binding to the molecular chaperones, BIPs.
Taken together, these data suggest that the integrity of the EF hand motif in Hevin is crucial for correct folding and that ASD-related mutations impair Hevin export from the ER.
Our data provide a novel mechanism linking a point mutation in the SPARCL1 gene with molecular and cellular characteristics involved in ASD.