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"Autism gene" causes problems in the composition of synapses

A new finding in the field of autism research has attracted the attention of the scientific world. Although the international group of researchers that published the findings in the renowned journal Nature have so far only managed to switch off two genes in mice, the animals’ conspicuous behaviour change has nevertheless made the scientific world sit up and listen. It appears that the enigmatic neuropsychiatric disease could have a genetic component. The first author of the study is Michael Schmeisser from the group of researchers led by Tobias Böckers at the Institute of Anatomy and Cell Biology at Ulm University.

Autism is a general term for a group of complex disorders of brain development. Autism usually presents during childhood with features such as social isolation, impaired verbal and nonverbal communication and stereotyped behaviours. The genetic causes of autism remain largely unknown. However, there is increasing evidence that disruptions in neuronal junctions (i.e. synapses through which the neurons communicate with each other) in the central nervous system could cause autism to develop. These junctions are stabilised by structural proteins, including the ProSAP1/Shank2 protein. In order to understand the effect that this protein has on synapses and ultimately in the development of autism, the researchers genetically modified mice and disabled the relevant protein. Prior to the study published in Nature, some of the scientists involved had found evidence that the mutation of this protein can lead to autism in humans.

Scaffold protein directly affects synapses in the brain

The researchers were able to show that the scaffold protein ProSAP1/Shank2 has a direct influence on neuronal synapses. The genetic deletion of ProSAP1/Shank2 in the mouse model resulted in increased levels of related scaffold ProSAP1/Shank3 proteins at the synapses. The researchers also found elevated quantities of specific glutamate receptors (NMDA) at the synapses, which the first author of the study, Michael Schmeisser, believes has an effect on the correct maturation of the synapses. Postsynaptic density (PSD) Shank proteins link neurotransmitter receptors with each other and are also connected to the actin cytoskeleton; these proteins are referred to as “master scaffolding molecules” because they interact with many other PSD proteins. Glutamate is the most important biochemical transmitter of excitatory synapses.

Sister proteins with opposing effects

The comparison of ProSAP1/Shank2 with the “hot autism candidate gene” ProSAP1/Shank3 provided the researchers with another important finding. The sister protein also led to changes in the molecular composition of synapses when the corresponding gene was deleted in the animal model.

The study suggests that ProSAP1/Shank2 and ProSAP1/Shank3 have different, interrelated roles at the excitatory synapses. However, the researchers from Ulm still need to identify the exact molecular mechanisms and “take into account the different abnormalities in synaptic glutamate receptor expression when developing appropriate therapies for autism,” said Tobias Böckers.

Michael Schmeisser finds it quite revealing that these genetic defects impair local processes while but do not affect the complete genome. The researchers therefore suggest that appropriate therapies should focus on the restoration of the structural order of the excitatory synapses rather than treating the underlying genetic defect.

Transgenic animals reveal autistic behaviour

The researchers’ findings can also be seen as a synaptic concert in which the genetic defect leads to the wrong notes being played. Although these “wrong notes” have no effect on other important synaptic functions (e.g. the regulation of breathing), they nevertheless impair higher brain functions. The finely tuned balance of synapses involved in control loops of facial recognition and social interaction is severely affected, resulting in autistic behaviour such as that displayed by mice that lack this particular gene.

However, final evidence as to which brain regions are affected is still missing as the authors of the Nature study focused specifically on the molecular imbalances at so-called glutamatergic synapses.

Colour-coded visualization of protein levels in mouse brains in which the ProSAP1/Shank2 and ProSAP2/Shank3 genes were switched off in the cortex, hippocampus and striatum at the indicated time points (P25, P70). The figure shows that the molecular protein composition at the glutamatergic synapses in these brain regions is affected to different extents. According to Michael Schmeisser, the extent of abnormalities also depends on the developmental stage of the animals. The research suggests that the synapses of genetically modified mice are characterized by molecular maturation defects. © Böckers/Schmeisser, University of Ulm

Böckers: Psychiatry becomes molecular

Over the last few years, researchers around the world have shown that autism has a genetic component and that several gene mutations increase the risk of developing autism. “This is something new and psychiatrists need to work with this new reality,” Böckers commented, aware that the increasing evidence supporting the observation that autism has genetic causes represents a kind of paradigm change in the field of neuropsychiatry.

Although the disease is classified according to international standards, there is no standard autism disease that can be clearly differentiated from other diseases. This is why autistic-like behaviours are generally referred to as autism spectrum disorders (ASD). The research community has identified three core characteristics associated with autism, all of which vary to some extent from one ASD to another – a qualitative impairment in social interactions (e.g. lack of eye contact), a qualitative impairment in communication (e.g. speech disorders up to mutism) and restricted or stereotyped pattern of activities of motoric nature (e.g. hand wringing/washing).

Around five percent of autism spectrum disorders are the consequence of a single gene deletion

Researchers from the Ulm-based Institute of Anatomy and Cell Biology who were involved in the Nature study: Tobias Böckers, Andreas Grabrucker, Patrick Udvardi, Jürgen Bockmann, Michael Schmeisser (back row on the left); the photo also shows Elodie Ey (Paris) and Anna Lena Jansen (front row on the left) © University of Ulm

Tobias Böckers has observed over a period of around five years that three to five percent of ASDs have a monogenetic cause. The majority of the 15 genes that are thought to play a key role in the development of ASD are structural proteins at synapses.

However, little is known about the causes of the majority of ASDs. Böckers, who is a medical doctor, believes it will take another five to ten years before medical researchers are able to reveal the causes of ASD. Böckers expects that it will then be possible to differentiate individual ASDs and relate each specific disorder to specific gene defects. In the USA, advocacy organisations such as Autism Speaks are working on increasing the awareness of autism spectrum disorders and are funding research into the causes, prevention and treatment of autism. Europe is following this model and a consortium called the European Autism Research Consortium, which involves researchers like Böckers as well as pharmaceutical companies, was recently launched and is being given 32 million euros of funding by the Innovative Medicine Initiative for a period of five years.

The number of autistic diseases that have come to light has been increasing dramatically, which might partially be due to the fact that the US film “Rainman” increased public awareness and made the disease better known. The number of people affected by autism is somewhere between 1 in 100 and 1 in 1000 and it affects all racial groups.

Disease models are needed

At present, researchers around the world are working with disease models for defined neuropsychiatric disorders such as fragile X syndrome, which is the most common inherited cause of autism and has typical physical characteristics such as an elongated face and protruding ears, to name just two features. The company Seaside Therapeutics on the American East Coast is developing a drug for the treatment of this disease. The drug is currently undergoing clinical phase IIB testing. 

“What can we learn about autism from mice?” said Tobias Böckers, an experienced researcher who admits that he was initially quite sceptical about using mice for research into autism. But over time, he learned from the work with transgenic animals that “their system is not finely tuned enough for higher brain performances to occur”. Böckers and Schmeisser were intrigued by the results obtained by their colleague Elodie Ey from the Institut Pasteur in Paris who found that the ultrasound vocalizations of transgenic experimental animals differed from those of non-mutated mice. 

Böckers discovered the ProSAP1/Shank2 gene around 14 years ago and so he knows the gene’s physiological role quite well. It is a molecule that is involved in the structural and functional organization of synapses and it represents the platform on which the membrane-bound, densely packed glutamate receptors are retained and sorted spatially and temporally. 

Two formerly separate paths of scientific research came together in the synaptic molecule ProSAP1/Shank2, which brought together Böckers as basic researcher with the human genetics researcher Thomas Bougeron from the Institut Pasteur in Paris. Bougeron found mutated versions of ProSAP1/Shank2 in autistic people and in Böckers he found a new colleague who was able to explain the molecule from a basic researcher’s point of view. There is still a long way to go before researchers will be able develop an autistic disease model. Schmeisser is well aware that in-depth details about the physiological conditions and the molecule’s cell- and neurobiology need to be known before they can start looking for ways to treat the disease. 

Another important goal: development of therapies

First author of the Nature paper: 29-year-old Michael Schmeisser. © Pytlik

The researchers from Ulm are interested in finding out what happens when the genetic defects of the two mice (i.e. ProSAP1/Shank2 and ProSAP2/Shank3) are combined. With regard to the disease, this is a rather unphysiological procedure; however, it enables Schmeisser to determine the roles of the individual molecules and find out what happens when the animals lack both proteins. The researchers already know that double knockout mice (i.e. mice with ProSAP1/Shank2 and ProSAP2/Shank3 deletions) are able to survive, albeit the probability of survival is lower than for single mutants. The researchers also know that such mice display autistic behaviour. Böckers and Schmeisser hope to be able to develop a model that gives them better insights into the development of autistic behaviours, but they are all too aware that they have only just scratched the surface.

The Ulm researchers also hope to clarify which brain region is essential for the autism-like symptoms to occur and for this they will use local knockouts, i.e. tissue-specific gene knockouts. Once potential targets are identified, they will be able to breed mice with disease symptoms that can be allocated to a specific brain region (e.g. the striatum). 

Last not least, Schmeisser also plans to develop a therapeutic approach based on a natural modulator of synaptic density and maturity (insulin-like growth factor 2 (IGF2)) and subsequently pass it on to the pharmaceutical industry. Schmeisser will use IGF2 and drugs that are already on the market to treat specific transgenic mice. IGF2 is produced by healthy people in the brain and other tissues, which is why Schmeisser does not expect it to have any adverse effects. He believes that IGF2 has amazing potential for promoting the molecular maturation of synapses and he intends to carry out experiments to find out whether IGF2 has any effect and whether it can be used for treating ASD. The 29-year-old, who already holds a medical degree, is currently doing his doctorate (PhD) at Ulm University. The findings will have to be substantiated with further evidence before they can be passed on to research laboratories in pharmaceutical companies and developed into drugs. “We are basic researchers, and will continue focusing on what we do best,” Schmeisser said, referring to both himself and his mentor Tobias Böckers.

Schmeisser, Michael J., Ey, Elodie et al: Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. doi:10.1038/nature11015 (https://www.gesundheitsindustrie-bw.dewww.nature.com/nature/journal/vaop/ncurrent/full/nature11015.html)

Grabrucker, Andreas M., Schmeisser, Michael J. et al. Postsynaptic ProSAP/Shank scaffolds in the cross-hair of synaptopathies, doi:10.1016/j.tcb.2011.07.003 Trends in Cell Biology, October 2011, Vol. 21, No. 10.

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