The inner workings of a rare childhood disease
Vanessa Sanchez was the lead author on this study. As a scientist, Vanessa is passionate about understanding the cell biology of neurons, especially in the context of pediatric neurodevelopmental – degenerative disorders. Outside of lab, you can find Vanessa tending to her garden, trying new recipes, rock climbing, or hanging out with her cat, Jiji!
or technically,
Altered lipid homeostasis is associated with cerebellar neurodegeneration in SNX14 deficiency
[See Original Abstract on Pubmed]
Authors of the study: Yijing Zhou, Vanessa B Sanchez, Peining Xu, Thomas Roule, Marco Flores-Mendez, Brianna Ciesielski, Donna Yoo, Hiab Teshome, Teresa Jimenez, Shibo Liu, Mike Henne, Tim O'Brien, Ye He, Clementina Mesaros, Naiara Akizu
Neurons are special cells in our bodies that communicate with one another to help us do everyday things like eat, think and walk. Amazingly, for most healthy people, the neurons that we are born with will last our lifetimes and support us as we navigate the world. However, in some rare and unfortunate diseases, neurons die prematurely. These kinds of diseases are called neurodegenerative diseases. There are many different types of neurodegenerative disease, each targeting different groups of neurons and resulting in different symptoms. In 2014, a new and extremely rare neurodegenerative disease was discovered called SCAR20. SCAR20 was found to negatively affect newborn children by causing intellectual disability and impairing motor functions, like the ability to walk. Researchers were quickly able to identify the culprit of the disease: the total lack of a protein called SNX14. Since little is known about SNX14 and how its absence causes SCAR20, Vanessa Sanchez, a current NGG student, and her collaborators designed a study to learn more about the nature of this disease, with the hope that one day there might be a cure or treatment.
Figure 1. Key takeaways from Vanessa and colleagues’ experiments investigating the underlying causes of the SCAR20 disease.
To begin their investigation, Vanessa and her collaborators used genetic tools to remove the SNX14 protein from mice. Genetically modified mice are immensely useful in neuroscience research as they allow scientists to study the underlying causes of disease in detail. In this case, since the researchers removed a protein, the genetically modified mice are referred to as a knockout mouse model. After they generated their new knockout mice, Vanessa and her colleagues tested these mice to make sure that they had all of the symptoms that the children experienced. This was an important step in their study because they wanted to be sure that any discoveries that they make using the knockout mouse model are directly relevant for human patients. Vanessa and her colleagues compared the knockout mice to normal healthy mice and found a few convincing results (Figure 1, Healthy mouse vs. Knockout mouse). First, they found that knockout mice had a complete lack of SNX14 in their brains - the direct cause of SCAR20 in humans. Next, they found that knockout mice were smaller in size and had a structurally abnormal face - two known symptoms of SCAR20 in humans. Finally, they found that the knockout mice had worse social memory and motor ability compared to healthy mice - again, a clear-cut sign of SCAR20 in humans. Given these results, Vanessa and her colleagues were convinced that they had developed a good mouse model of the SCAR20 disease and were now able to investigate how the disease develops.
In order to gain insight into the underlying causes of the disease, Vanessa and her colleagues needed to narrow down their focus to a single brain area. In human patients, SCAR20 seems to preferentially kill neurons in a brain area known as the cerebellum. This brain area is typically thought to be involved in motor control and coordination, which might explain why SCAR20 patients have severe motor disability. Vanessa and her colleagues discovered that, just as in human SCAR20, the knockout mouse model also showed a preferential negative effect on the cerebellum of the mice. She found that both the number of neurons and the overall size of the cerebellum were reduced in the knockout mice compared to healthy mice, once again validating the model for the study of SCAR20 and identifying a key brain area to narrow in on.
At this point, Vanessa and her colleagues have all the tools they need to study the inner workings of the disease. They performed a very important experiment where they extracted neurons in the cerebellum of knockout mice before they were killed by the disease, and looked for differences compared to the neurons in the cerebellum of healthy mice (Figure 1, Healthy neuron vs. Knockout neuron). By testing various cell properties, they discovered that there was one key cell property that was disrupted in the neurons of knockout mice compared to the neurons of healthy mice. This key cell property is called lipid homeostasis, which is important for regulating lipids, the building blocks of fat, inside the cell. Despite what you may expect, fats play an essential role in cell biology. Disrupting the total amount of fats inside of the cell can be toxic, resulting in cell death. In fact, Vanessa and her colleagues discovered that knockout neurons had trouble removing fats from the cell, resulting in a build-up. They went on to show that this disruption in lipid homeostasis is most likely the root cause of neuron death in SCAR20, which underlies the known symptoms of the disease.
This important research by Vanessa and her colleagues sheds light on the inner workings of a new disease that severely impacts the well-being of newborn children. Although there is still much to learn about the nature of this disease, such as how it affects neurons in other brain areas, the findings from Vanessa’s experiments offer a strong foundation for the possible development of treatments for this debilitating disease. Finally, research like Vanessa’s is invaluable as it contributes to our basic understanding of how neurons work and what causes them to die prematurely - knowledge that is fundamental for all neurodegenerative diseases.
About the brief writer: [Brief writer’s name here]
Jafar Bhatti is a PhD Candidate in the lab of Dr. Long Ding / Dr. Josh Gold. He is broadly interested in brain systems involved in sensory decision-making.