Gender-biased protein may play role in autism: Mouse study

Summary: 204 proteins discovered were more highly regulated in females than males, with 31% of the proteins being associated with the development of Autism, researchers report. Findings shed new light on why males are at higher risk of ASD than females.

Source: Frontiers

Researchers at the University of New Hampshire are one step closer to helping answer the question of why autism is four times more common in boys than in girls after identifying and characterizing the connection of certain proteins in the brain to autism spectrum disorders (ASD).

“Our study is the first to look at the gender-biased regulation of proteins in the brain and how they may play a role in affecting abnormal changes in the body that results in autism,” said Xuanmao (Mao) Chen, assistant professor of neurobiology. “Our findings point to a new direction for autism research and suggest promising possibilities for creating novel treatment strategies.”

This shows a little boy and girl
What is known is that many neurodevelopmental disorders or psychiatric diseases, such as depression and autism, exhibit profound differences between males and females, known as sexual dimorphism. Public domain image.

In the study, recently published in the journal Frontiers in Cellular Neuroscience, the researchers looked at an enzyme called AC3 which is genetically connected to major depressive disorder (MDD), obesity, and autism spectrum disorders (ASD). However, not much is known about how AC3 functions in the brain. What is known is that many neurodevelopmental disorders or psychiatric diseases, such as depression and autism, exhibit profound differences between males and females, known as sexual dimorphism. For example, females have a higher risk of depression, whereas autism affects more males, with a boy to girl ratio of four to one. The problem is that it is unclear what causes the differences.

The researchers took a closer look at the phosphorylation in the brain, a process when groups of chemicals called phosphates attach to proteins to regulate them, to see which were influenced based on gender. They identified 204 proteins that were more highly regulated in females than in males. Of those, a large percentage (31%) were associated with autism.

“Our results suggest that proteins in the female brain, particularly autism-related proteins, are more tightly regulated than those in the male brain possibly helping to prevent the development of autism in females,” said Chen.

The researchers point to evolution for possibly playing a part in how these proteins behave based on the key roles or functions of each sex. The female role has traditionally been multi-tasking several activities like childrearing, caring for the family, the home, and preparing meals whereas male tasks were more specifically focused on functions like hunting and gathering. You can see this highly focused trait in autistic males who are very smart but tend to be fixated on one thing and not interested in, or cannot handle, other social interactions.

Chen says that this research is still in the early phase with mouse models and more studies are needed, but he is hopeful that it may open up a new research direction and one day could possibly lead to a new pharmacological treatment.

About this neuroscience research article

Media Contacts:
Xuanmao (Mao) Chen – Frontiers
Image Source:
The image is adapted from the Frontiers news release.

Original Research: Open access
“Comparative Phosphoproteomic Profiling of Type III Adenylyl Cyclase Knockout and Control, Male, and Female Mice”. Yuxin Zhou, Liyan Qiu, Ashley Sterpka, Haiying Wang, Feixia Chu and Xuanmao Chen.
Frontiers in Cellular Neuroscience. doi:10.3389/fncel.2019.00034


Comparative Phosphoproteomic Profiling of Type III Adenylyl Cyclase Knockout and Control, Male, and Female Mice

Type III adenylyl cyclase (AC3, ADCY3) is predominantly enriched in neuronal primary cilia throughout the central nervous system (CNS). Genome-wide association studies in humans have associated ADCY3 with major depressive disorder and autistic spectrum disorder, both of which exhibit sexual dimorphism. To date, it is unclear how AC3 affects protein phosphorylation and signal networks in central neurons, and what causes the sexual dimorphism of autism. We employed a mass spectrometry (MS)-based phosphoproteomic approach to quantitatively profile differences in phosphorylation between inducible AC3 knockout (KO) and wild type (WT), male and female mice. In total, we identified 4,655 phosphopeptides from 1,756 proteins, among which 565 phosphopeptides from 322 proteins were repetitively detected in all samples. Over 46% phosphopeptides were identified in at least three out of eight biological replicas. Comparison of AC3 KO and WT datasets revealed that phosphopeptides with motifs matching proline-directed kinases’ recognition sites had a lower abundance in the KO dataset than in WTs. We detected 14 phosphopeptides restricted to WT dataset (i.e., Rabl6, Spast and Ppp1r14a) and 35 exclusively in KOs (i.e., Sptan1, Arhgap20, Arhgap44, and Pde1b). Moreover, 95 phosphopeptides (out of 90 proteins) were identified only in female dataset and 26 only in males. Label-free MS spectrum quantification using Skyline further identified phosphopeptides that had higher abundance in each sample group. In total, 204 proteins had sex-biased phosphorylation and 167 of them had increased expression in females relative to males. Interestingly, among the 204 gender-biased phosphoproteins, 31% were found to be associated with autism, including Dlg1, Dlgap2, Syn1, Syngap1, Ctnna1, Ctnnd1, Ctnnd2, Pkp4, and Arvcf. Therefore, this study also provides the first phosphoproteomics evidence suggesting that gender-biased post-translational phosphorylation may be implicated in the sexual dimorphism of autism.

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