Gender-biased regulation of proteins in the brain – new direction for autism research


Autism is a lifelong neuropsychiatric condition first apparent during early development that is characterized by social and communication deficits and by repetitive behaviors and restricted interests.

The severity and variety of symptomatic behaviors, impairments, and abilities that autistic individuals show is vast, leading to the formal conceptualization of autism as a spectrum (autism spectrum disorder, ASD) [1].

ASDs also differ by sex, with a striking and consistent male bias in prevalence [23].

In recent years, interest in investigating sex differences in the autistic phenotype and exploring a potential need for sex-differential diagnostic criteria has grown more widespread [45].

At the same time, research findings and public discourse have challenged the magnitude of the male bias in prevalence [610], and genetics studies have demonstrated patterns of risk variation that are consistent with a protective effect against the ASD phenotype in females [1121].

Work to identify the sex-differential factor(s) responsible for this protection has returned several potential leads, but the key factor(s) involved remains unknown, and the molecular, cellular, and/or neurodevelopmental pathway(s) by which these factors impact risk are not currently understood.

Given the strong impact of sex on ASD prevalence and/or presentation, understanding the points of interaction between sex-differential factors and ASD etiological pathways is likely to reveal critical aspects of ASD biology that may provide effective therapeutic targets.

More and continued attention to these questions, particularly with input from the sex differences research community, is warranted to begin to make concrete sense of the ways that sex-differential neurodevelopment and brain function modulate neuropsychiatric risk.

Here, I aim to summarize the current state of research findings on sex differences in ASD prevalence, phenotype, and risk mechanisms, as well as to highlight gaps in our current understanding that are likely to benefit from input from the sex differences research community.

Autism prevalence is male-biased

The most striking sex difference in ASD is its prevalence, as approximately four times as many males have a diagnosis of ASD as females [2].

This 4:1 male:female ratio is a commonly cited statistic that represents a consensus across epidemiological studies conducted in different countries, at different times, and using different iterations of diagnostic criteria; on an individual study level, the degree of male skew can vary widely.

Though recent in-depth prevalence studies have tended to report smaller male biases than the 4:1 estimate [6810], ASD-diagnosed males consistently predominate across these and earlier epidemiological surveys [23], making sex-biased prevalence one of the most temporally and geographically stable features of ASDs.

At face value, this pattern of disparate prevalence suggests the action of sex-differential risk factors for ASD that act to either increase males’ risk and/or protect females.

Just a few decades ago, as our conceptualization of ASD shifted from the domain of psychoanalysis to neuropsychiatry and genetics, an assumption that sex-differential risk factors were also biological in nature followed suit [2223].

More broadly, this paradigm shift and the dismissal of parenting style as the cause of ASD (so-called “refrigerator mothers” [2425]) revealed gaps in our knowledge of autism that researchers have aimed to fill.

For much of the field, top priority questions included characterizing the behaviorally defined autistic phenotype in neuroscientific terms, particularly from the cognitive neuroscience [2627] and structural/functional neuroanatomical perspectives [2831], with the intention to leverage these descriptions to discover ASD’s underlying causes.

During this time, a handful of research groups published studies that compared males and females with ASD on the presentation and severity of their autism symptoms [3235] or on neuroanatomical features [3637].

However for a majority of analyses, despite the male skew in ASD’s prevalence, sex was most frequently considered a variable to control for, not an aspect of risk to investigate in its own right.

Often, to reduce experimental variability, characterization studies of autistic behavior, cognition, neuroimaging, and neuroanatomy only included male participants with ASD.

Still, despite more widespread focus on characterizing the autistic phenotype and its cause(s), the hypothesis that some aspect of male and/or female biology modulates ASD risk remained.

Several research groups proposed the involvement of general sexually dimorphic factors such as X-linkage [3839], imprinting [4041], and sex steroid hormone levels [42].

However, another, non-mutually exclusive possibility is that females are affected by ASD at higher rates than previously thought, but that they are not being diagnosed.

If this scenario were true, it would require a careful reexamination of the ASD phenotype, our understanding of which is based on the study of majority male cohorts, as well as our assumptions about sex-differential risk and protection for ASD.

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.

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


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