The research was led by Tel Aviv University’s Prof. Abdussalam Azem, Dean of the Wise Faculty of Life Sciences, in collaboration with Prof. Uri Ashery and PhD student Eyal Paz from the School of Neurobiology, Biochemistry and Biophysics at the Wise Faculty of Life Sciences and the Sagol School of Neuroscience. Additional contributors included Dr. Sahil Jain and Dr. Irit Gottfried from the School of Neurobiology, Biochemistry, and Biophysics at Tel Aviv University, Dr. Orna Staretz-Chacham from the Faculty of Health Sciences at Ben-Gurion University, Dr. Muhammad Mahajnah from the Technion, and researchers from Emory University in Atlanta, USA. The findings were published in the prominent journal eLife.

TIMM50 Mutation Linked to Rare Brain Disorders

Prof. Azem explains: "The disease we studied is caused by a mutation in a protein called TIMM50, which plays a crucial role in importing other proteins into the mitochondria—the organelle considered the cell's energy powerhouse. The human mitochondria operate with about 1,500 proteins (approximately 10% of all human proteins), but only about 13 of them are produced within the mitochondria itself. The rest are imported externally through various mechanisms. In recent years, mutations in the TIMM50 protein, which is responsible for importing about 800 proteins into the mitochondria, were found to cause severe and rare neurological disease with symptoms like epilepsy, developmental delay, and intellectual disability".

Prof. Ashery adds: "Protein import into the mitochondria has been extensively studied over the years, but how a mutation in TIMM50 affects brain cells was never tested before. To investigate this for the first time, we created an innovative model using mouse neurons that mimics the disease caused by the TIMM50 protein mutation. In this study, we significantly reduced the expression of the protein in mouse brain cells and observed its impact on the cells".

How Does a Protein Defect Link Energy Loss to Epilepsy?

Eyal Paz explains: "The impairment of the protein led to two main findings: a reduction in energy production in the neurons, which could explain the developmental issues seen in the disease and an increase in the frequency of action potentials (the electrical signals that transmit information along neurons and enable communication between them). This increase in action potential frequency is known to be associated with epilepsy. The change in frequency is likely caused by significant damage to two proteins that function as potassium channels. Imbalances in potassium levels can lead to life-threatening conditions, such as arrhythmias, cardiac arrest, and muscle weakness, potentially leading to paralysis. These potassium channels may serve as potential targets for future drug treatments for the disease".

Prof. Azem concludes: "Our study decodes the mechanism of a severe and rare neurological disease caused by a mutation in a protein critical for importing proteins into the mitochondria. Understanding the mechanism is a crucial step toward treatment, as it enables the development of drugs targeting the specific issues identified. Additionally, we created a new research model based on mouse neurons that significantly advances the study of protein import into mitochondria in brain cells. We believe that our findings, combined with the innovative model, will enable more in-depth research and the development of treatments for various neurological diseases caused by similar mitochondrial dysfunction mechanisms".

The study was led by Dr. Bat-El Pinchasik from the School of Mechanical Engineering and Prof. Amir Ayali from the School of Zoology at the Wise Faculty of Life Sciences, the Sagol School of Neuroscience and the Steinhardt Museum of Natural History at Tel Aviv University. Other participants included: PhD student Shai Sonnenreich from TAU's School of Mechanical Engineering, as well as researchers from the Technical University of Dresden in Germany, Prof. Yael Politi and a postdoc in her group, Dr. Andre Eccel Vellwock. The article was published in the prestigious journal Advanced Functional Materials.

Left to right: Prof. Amir Ayali, Dr. Bat-El Pinchasik & PhD student Shai Sonnenreich.

Dr. Pinchasik: “In my lab, we study mechanical mechanisms in nature, partly to draw inspiration for solving technological problems. Recently we collaborated with locust expert Prof. Amir Ayali in a series of studies, to understand the mechanism used by the female locust for digging a pit to lay her eggs. This unique mechanism consists of two shovel-like valves that open and close cyclically, digging into the soil while pressing the sand against the walls”.

Prof. Ayali: “We know that many mechanisms in the bodies of insects in general, and locusts in particular, are exceptionally resistant to mechanical wear. For example, the locust's mandibles, used daily for feeding, are made of a highly durable material. The digging valves, on the other hand, while subjected to substantial shear forces during digging, are used only 3 or 4 times in the female's lifetime - when she lays eggs. In this study, we sought to discover whether these digging valves, made of hard cuticular material, were also equipped by evolution with high resistance to mechanical wear”.

To address this question, the researchers examined the digging valves in three different groups of female locusts: young females that had not yet laid eggs, mature females kept in conditions that prevented them from laying eggs - to test whether age alone causes wear and adult females that had already laid eggs 3 or 4 times. To analyze the internal structure and durability of the digging valves, the researchers used several advanced technologies: confocal microscopy, 3D fluorescent imaging, and a particle accelerator (synchrotron) in collaboration with the German team. The findings indicated significant signs of wear in the valves and a lack of elements associated with high resistance to mechanical wear. Notably, no reinforcing metal ions, typical of extremely wear-resistant biological materials, were found in the valves.

Dr. Pinchasik: “A female locust's biological role is laying eggs three or four times in her life. In this study, we found that evolution has designed her digging valves to meet their task precisely—no more and no less. This is a wonderful example of the ‘good enough’ principle in nature: no extra resources are invested in an organ when they’re not needed".

“As humans, we can learn much from nature - about conserving materials, energy, and resources. As engineers who develop products, we must understand the need precisely and design an accurate response, avoiding unnecessary overengineering” - Dr. Pinchasik.

The surprising study was led by Dr. Natalia Kononov, who completed her doctorate under the supervision of Prof. Danit Ein-Gar at the Coller School of Management at Tel Aviv University and is now a postdoctoral fellow at the Wharton School of Business at the University of Pennsylvania. The study, conducted in collaboration with Prof. Ein-Gar and Prof. Stefano Puntoni of Wharton, was published in the International Journal of Research in Marketing.

Prof. Danit Ein-Gar (Photo credit: Israel Hadari).

“When we enhance our appearance and feel beautiful—for example, after a fresh haircut—we behave in a more socially conscious manner”, explains Prof. Ein-Gar. “Why? Because we feel as though all eyes are on us, drawing attention, and so we strive to act better. It’s easy to criticize the selfie generation, constantly beautifying themselves and sharing polished photos, but we demonstrate a side effect of this behavior that can benefit society. People who feel good about their appearance can channel that feeling into good deeds”.

Dr. Natalia Kononov.

To test their hypothesis, the researchers conducted a series of experiments, some in virtual settings and others in a laboratory. In one lab experiment, participants were asked to use a filter to enhance a selfie they had taken. A control group, meanwhile, was asked to enhance a photo of an object in the room.

“The experimental group consisted of 50 participants, as did the control group”, Prof. Ein-Gar explains. “After viewing their enhanced photo, each participant collected an envelope with their payment in cash. Next to the payment envelope, there was a donation box so participants could voluntarily donate some or all of their payment. We observed that members of the experimental group, who saw themselves as more attractive, donated up to twice as much as those in the control group. It’s enough to imagine ourselves as more attractive—even just envisioning a more polished digital version of ourselves—to encourage prosocial behavior. This insight has significant practical implications. Until now, research has focused on the appearance of the donation seekers—whether the recipient or the fundraiser—and indeed, more attractive fundraisers have been found to raise more money. Our study introduces another relevant factor: the donor’s appearance. This opens the door to innovative strategies for streamlining charity campaigns, such as partnering with cosmetic companies, hairdressers, and beauty salons—for everyone’s benefit”.

Beauty and the Benefit

One of the most surprising experiments was conducted virtually, on Facebook. Clicking on a link randomly directed users to one of two “know yourself” questionnaires. The control group’s questionnaire asked about preferred architectural styles, while the experimental group’s questionnaire included questions about fashion styles and was designed to make respondents imagine themselves at their most attractive moments, such as envisioning themselves dressed up for a fancy social event. At the end of the questionnaire, a seemingly unrelated pop-up appeared with a link to a donation page. About 7% of respondents who answered the “beauty” questionnaire clicked on the donation link, compared to approximately 2% of those who answered the architectural questionnaire—a particularly impressive figure considering the average click-through rate on Facebook links is just 0.9%.

“Our society is obsessively focused on physical appearance while simultaneously criticizing this superficial behavior”, says Dr. Kononov. “People who are appearance-focused are often judged harshly, but we show that this behavior can have positive spillover effects that benefit others. Social mechanisms may evolve to create some balance, where behaviors that serve the individual are accompanied by byproducts that contribute to the greater good“.

The study was led by the lab of Prof. Boaz Barak and PhD student Inbar Fischer from the Sagol School of Neuroscience and the School of Psychological Sciences at Tel Aviv University, in collaboration with the labs of Prof. Ben Maoz from the Department of Biomedical Engineering at Fleischman Faculty of Engineering at Tel Aviv University and Prof. Shani Stern from the Department of Neurobiology at the University of Haifa. The article was published in the prestigious journal Science Advances.

PhD student Inbar Fischer.

Prof. Barak: "Autism is a relatively common neurodevelopmental disorder. According to current data, 1-2% of the global population and one in every 36 boys in the U.S. are diagnosed with autism spectrum disorder (ASD), with numbers rising over time. Autism is caused by a wide range of factors - environmental, genetic, and even social and cultural (such as the rise in parental age at conception). In my lab, we study the genetic causes of autism. Among these are mutations in a gene called SHANK3. The impact of these mutations on the function of brain neurons has been extensively studied, and we know that the protein encoded by SHANK3 plays a central role in binding receptors in the neuron, essential for receiving chemical signals (neurotransmitters and others) by which neurons communicate. Thus, damage to this gene can disrupt message transmission between neurons, impairing the brain's development and function. In this study we sought to shed light on other, previously unknown mechanisms, through which mutations in the SHANK3 gene disrupt brain development, leading to disorders manifested as autism".

Specifically, the research team focused on two components in the brain that have not yet been studied extensively in this context: non-neuronal brain cells (glia) called oligodendrocytes and the myelin they produce. Myelin tissue is a fatty layer that insulates nerve fibers (axons), similar to the insulating layer that coats electrical cables. When the myelin is faulty, the electrical signals transmitted through the axons may leak, disrupting the message transmission between brain regions and impairing brain function.

How a Gene Mutation Impacts the Brain

The team employed a genetically engineered mouse model for autism, introducing a mutation in the Shank3 gene that mirrors the mutation found in humans with this form of autism. Inbar Fischer: "Through this model, we found that the mutation causes a dual impairment in the brain's development and proper function: first, in oligodendrocytes, as in neurons, the SHANK3 protein is essential for the binding and functioning of receptors that receive chemical signals (neurotransmitters and others) from neighboring cells. This means that the defective protein associated with autism disrupts message transmission to these vital support cells. Secondly, when the function and development of oligodendrocytes is impaired, their myelin production is also disrupted. The faulty myelin does not properly insulate the neuron’s axons, thereby reducing the efficiency of electrical signal transmission between brain cells, as well as the synchronization of electrical activity between different parts of the brain. In our model, we found myelin impairment in multiple brain areas and observed that the animals' behavior was adversely affected as a result".

The researchers then sought a method for fixing the damage caused by the mutation, with the hope of ultimately developing a treatment for humans. Inbar Fischer: "We obtained oligodendrocytes from the brain of a mouse with a Shank3 mutation, and inserted DNA segments containing the normal human SHANK3 sequence. Our goal was to allow the normal gene to encode a functional and normal protein, which, replacing the defective protein, would perform its essential role in the cell. To our delight, following treatment, the cells expressed the normal SHANK3 protein, enabling the construction of a functional protein substrate to bind the receptors that receive electrical signals. In other words, the genetic treatment we had developed repaired the oligodendrocytes' communication sites, essential for the cells’ proper development and function as myelin producers".

To validate findings from the mouse model, the research team generated induced pluripotent stem cells from the skin cells of a girl with autism caused by a SHANK3 gene mutation identical to that in the mice. From these stem cells, they derived human oligodendrocytes with the same genetic profile. These oligodendrocytes displayed impairments similar to those observed in their mouse counterparts.

Autism and Myelin Damage: New Hope for Treatment

Prof. Barak concludes: "In our study, we discovered two new brain mechanisms involved in genetically induced autism: damage to oligodendrocytes and, consequently, damage to the myelin they produce. These findings have important implications – both clinical and scientific.  Scientifically, we learned that defective myelin plays a significant role in autism and identified the mechanism causing the damage to myelin. Additionally, we revealed a new role for the SHANK3 protein: building and maintaining a functional binding substrate for receptors critical for message reception in oligodendrocytes (not just in neurons). We discovered that contrary to the prevailing view, these cells play essential roles in their own right, far beyond the support they provide for neurons — often seen as the main players in the brain. In the clinical sphere, we validated a gene therapy approach that led to significantly improved development and function of oligodendrocytes derived from the brains of mice modeling autism. This finding offers hope for developing genetic treatment for humans, which could improve the myelin production process in the brain. Furthermore, recognizing the significance of myelin impairment in autism—whether linked to the SHANK3 gene or not—opens new pathways for understanding the brain mechanisms underlying autism and paves the way for future treatment development".