Summary: Researchers report that an autism-associated mutation in the extracellular matrix protein Hevin disrupts its folding and secretion, increasing splicing errors and triggering endoplasmic reticulum stress via activation of the unfolded protein response.
Source: University of Tsukuba
A common disruption in everyday life—getting stuck in a traffic jam—serves as an illustrative analogy for a newly described cellular problem. Scientists at the University of Tsukuba show that an autism-associated mutation can create a cellular “traffic jam” by causing unfolded or misfolded Hevin protein to accumulate in the endoplasmic reticulum (ER), thereby disturbing normal neuronal processes.
Published in Scientific Reports, this study explores how mutations affecting Hevin (also known as SPARCL1), a secreted extracellular matrix protein that contributes to synapse formation and plasticity, interfere with its normal processing and export from the ER.
While many gene variants linked to autism spectrum disorder (ASD) have been catalogued, the precise cellular consequences of many of these mutations remain unclear. The researchers focused on how defects in splicing and subsequent alterations to Hevin contribute to cellular stress pathways in the brain.
“We previously found that mutation of the Usp15 gene, which is closely associated with autism, increases the likelihood of splicing errors and activates the unfolded protein response, causing ER stress,” explains Professor Fuminori Tsuruta. “In this study we sought to determine which downstream proteins are affected and how those changes lead to ER dysfunction.”
The team screened for autism-linked variants that showed abnormal splicing in mouse brains lacking functional Usp15. They discovered Hevin transcripts frequently lacked the C-terminal region that contains the EF-hand motif, a structural element critical for proper folding and function. Notably, a point mutation affecting the EF-hand motif has been reported in a familial case of autism.
Functional analysis of both deletion mutants (missing the EF-hand motif) and a single amino acid substitution in the EF-hand revealed the same outcome: faulty Hevin folding that prevented normal secretion. Both classes of mutant Hevin accumulated in the ER and activated the unfolded protein response, a core cellular pathway that senses misfolded proteins and attempts to restore protein homeostasis.
Structural modeling and molecular dynamics simulations provided insight into why this occurs. The familial autism-associated substitution—a single change of tryptophan to arginine at a conserved position—exposes hydrophobic residues on the protein surface. This exposure destabilizes the Hevin structure and increases interactions with ER chaperones such as BiP, which retain the protein in the ER rather than allowing it to advance through the secretory pathway.
Professor Tsuruta summarizes: “These results indicate that the EF-hand motif is essential for Hevin to fold correctly and exit the ER. Mutations that disrupt this motif can therefore trigger ER retention and stress responses that may impair neuronal function.”
This mechanism echoes observations for other ASD-linked mutations that cause synaptic proteins to accumulate in the ER. Persistent ER stress and chronic activation of the unfolded protein response can alter neuronal health, synapse formation, and circuit function—factors that are plausibly connected to ASD-related neural changes.
Future work will be needed to trace how ER stress provoked by misfolded synaptic proteins affects neural circuits and overall brain homeostasis, and to clarify whether these molecular events directly contribute to 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: Open access.
“Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability” by Takumi Taketomi et al. Scientific Reports
Abstract
Autism-associated mutation in Hevin/Sparcl1 induces endoplasmic reticulum stress through structural instability
Hevin, encoded by SPARCL1, is a secreted extracellular matrix protein that contributes to synaptogenesis and synaptic plasticity. Variants in SPARCL1 are linked to increased ASD risk, but the molecular mechanisms behind this association have not been fully defined. In this study, researchers show that specific SPARCL1 mutations impair Hevin secretion and promote its retention in the ER.
By analyzing mice with compromised spliceosome function, the team identified Hevin mutants lacking the EF-hand motif. Those deletion mutants accumulated in the ER and activated unfolded protein responses, indicating ER stress. A familial ASD-associated point mutation (Trp647 to Arg) within the EF-hand produced a similar outcome.
Molecular dynamics simulations suggested that the single amino acid substitution exposes hydrophobic residues on Hevin’s surface, destabilizing its structure and increasing binding to ER chaperones such as BiP. These findings indicate that an intact EF-hand motif is essential for proper Hevin folding and export from the ER, and that ASD-associated mutations can compromise this process.
Collectively, the data provide a mechanistic link between a point mutation in SPARCL1 and cellular features—ER retention, unfolded protein response activation, and disrupted secretion—that may contribute to ASD pathophysiology.