Brain Awareness Week: Clemson scientists are studying neurological diseases that affect children and adults

The brain is the most important organ in the human body.

It is our command center, controlling everything from memory and movement to basics like the beating of your heart and breathing. Without a healthy brain, daily life becomes more difficult or even impossible.

To recognize  Brain Awareness Week, going on March 10-16, the Clemson University College of Science highlights three of its scientists who are conducting critical research on the brain and neurological disorders.

David Feliciano

Tuberous sclerosis complex (TSC) is a rare genetic disease caused by a mutation in one of two genes that are believed to prevent cells from growing out of control.

It can lead to noncancerous tumors throughout the body, seizures and a wide range of neurological and other organ symptoms, including autism spectrum disorder and other developmental disabilities. Symptoms often begin during the first year of a child’s life. 

David Feliciano, a developmental neurobiologist and an associate professor in the Clemson University Department of Biological Sciences, is working to unlock the mystery of this rare disease, which affects about one in 6,000 births.

Single mutation

TSC is caused by a mutation of one of two genes, TSC1 or TSC2. 

Abnormalities in the brains of patients with TSC can block the flow of cerebrospinal fluid and cause hydrocephalus.  

“Hydrocephalus can induce seizures and cause all kinds of other complications — headaches, migraines, and it can be fatal,” Feliciano says.  

Using mice, Feliciano’s lab discovered that the removal of one gene associated with TSC, TSC2, caused uncontrolled protein expression and overgrown cells, resulting in the kinds of brain abnormalities seen in patients. Following this discovery of the impact of the TSC2 gene in the developing brain, he started working on a pre-clinical study to develop a drug that targets uncontrolled translation that is currently under review.

“I think there’s more and more hope, not just for a treatment, but for an actual cure. Those patients that are so severely affected, that have hundreds of seizures by the time they’re young babies, may have a shot at living a healthy life. I think the trajectory is very promising,” Feliciano said.

He also paired up with Trudy Mackay, director of the Clemson Center for Human Genetics, to create single-cell RNA sequencing to find which individual cell types are present in the brain abnormalities and to study underlying cellular mechanisms further. The Department of Defense and the TSC Alliance, an advocacy organization for those affected by the condition, funded the development of this novel study. 

Feng Ding

Nearly 7 million people in the United States over the age of 65 have Alzheimer’s disease. Another million have Parkinson’s. Amyotrophic lateral sclerosis (ALS) affects up to three people per 100,000. 

All these diseases are neurodegenerative diseases that progress with age and can impact memory, neural functioning and behavior. They have a common molecular mechanism that leads to disease onset called amyloid aggregation.

Using novel computer modeling, Feng Ding, a professor in the Clemson Department of Physics and Astronomy, researches amyloid aggregation. Amyloids are fibrous proteins that typically do not clump together. However, when the protein misfolds, the proteins become sticky and aggregate, forming a deposit leading to brain disorders. 

Ding’s lab focuses on understanding the amyloid formations. 

Discrete molecular dynamics

He focuses on the structure and dynamics of the aggregation pathway by using a method called discrete molecular dynamics, a molecular modeling tool used to study large systems over a long period, typically something that is difficult to study.  Ding developed this method while in graduate school and continued working on the program in his postdoctoral studies.

Ding can model specific molecular structures, from the initial aggregating interactions to how the proteins evolve and spread. Researchers struggle to study this process in humans due to the long-term nature of aging diseases. 

When studying aggregating diseases, it’s nearly impossible to replicate human physiological conditions in test-tube experiments. Computer, or in-silico, testing can create new possibilities for studying aggregating diseases.

Ding’s lab focuses on a process called seeding. Seeding is the coaggregation of amyloids that allows a mutated protein to move to a different part of the brain, causing non-aggregating proteins to start aggregating and spreading the disease. 

Ding and his lab recently published a paper on the gene BRI2, which is anti-correlated with Alzheimer’s. Expression of this gene prevents amyloid accumulation and can slow down the progression of Alzheimer’s.

Using their molecular modeling tool and the study of BRI2, Ding’s lab has started to design engineered nanoparticles that can be used medicinally to slow down the aggregation process. 

Alzheimer’s disease, Parkinson’s, ALS and other diseases all involve mutations that lead to protein aggregation in molecular pathways. Interestingly, these diseases have co-pathology so that one can lead to another. For example, Type 1 diabetes patients have a higher chance of developing Alzheimer’s because the protein aggregating results in diabetes in the pancreas spreading to the brain through the seeding process. 

Ding has partners that test his theories in vitro or mice. “Sometimes we try to help them understand what’s going on at the molecular level, and there are also many cases where we make predictions, and they test them for us. So, this is a mutual interest,” Ding says.

Tara Doucet-O’Hare

Eight percent of human DNA comes from viruses. 

Endogenous retroviruses are viruses that reverse transcribe themselves and insert their DNA into the genome of the host organism they’re infecting. If a retrovirus infects an egg or sperm cell, the virus’s DNA could be inherited in the next generation.

Tara Doucet-O’Hare, an assistant professor in the Department of Genetics and Biochemistry and a member of the Clemson Center for Human Genetics, studies dysfunctional chromatin remodeling’s impact on endogenous retrovirus expression and neural development. Chromatin remodeling is a process that regulates gene expression by making DNA more or less accessible to transcription factors depending on the chromatin structure.

She looks at how this incorporated DNA can lead to different cancers when mutated, such as clear cell meningioma and atypical teratoid rhabdoid tumors in the brain.

“These tumors tend to affect really young children. There are no targeted treatment options currently, and it’s hard enough for an adult to live through all of those things, let alone a young child,” she said.

Process gone wrong

At specific points during development, the DNA needs to be accessible and then closed off again to halt the production of proteins. If this process goes wrong, one consequence could be uncontrolled cell growth or tumors. 

Doucet-O’Hare has recently worked with a retroviral protein called an envelope protein, which is expressed on the membrane of cells and exported in extracellular vesicles. When mutations occur in the chromatin remodeling proteins, the envelop gene can be expressed when it’s supposed to be turned off, resulting in cancerous cells. This protein is more prevalent in cancerous brain cells. 

“I showed if you knock out this protein in tumor cells, then you could essentially stop them from dividing so quickly and kill them,” Doucet-O’Hare said. 

She and her colleagues at the National Institutes of Health have recently found a peptide that targets the envelope protein and is starting a pre-clinical trial with the National Cancer Institute and a neurosurgeon at the University of Miami to test its use as medicine. 

Endogenous retroviruses were first discovered in chickens in the 1960s.

Similar development

Doucet-O’Hare uses chicken embryos, which she obtains from the Clemson poultry farm, to model the migration of cells throughout development and to investigate the endogenous retrovirus life cycle because chickens develop similarly to humans. 

The chicken embryo model also comes into use for the connection between retroviral proteins and chromatin remodeling. Doucet-O’Hare can inject DNA right into the embryonic cells to alter proteins and study how cells move and change during development in organisms’ standard nervous systems versus diseased nervous systems. She looks at which mutations lead to tumors and how different mutations impact tumor location, cell origin and size.

Doucet-O’Hare is also plans to experiment with exposing the embryos to different carcinogens like BPA in plastics to see the downstream consequences on development in the future.