University of South Florida

Research at USF Health reveals ALS and FTD gene link to pathology

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two rare neurodegenerative diseases also considered as spectrum disorders, affect thousands of Americans every year.

ALS, a condition that effects nerves and muscles, and FTD, a disorder that causes changes in behavior and personality, language, motor skills and function, are associated with one another due to a common genetic mutation in multiple genes.

David Kang, PhD, professor of molecular medicine, in his laboratory at the USF Health Byrd Alzheimer’s Institute. He was the study’s lead author. 

However, researchers did not know exactly why that happened until a new research breakthrough at University of South Florida Health in Tampa, Florida.

A group of USF Health researchers found that a mutated ALS and FTD gene is pathologically linked to mitochondria dysfunction and TDP-43 pathology – causing problems for people affected by either disease.

The results of this study were published in Nature Communications Journal.

The study’s lead investigator David Kang, PhD, professor of molecular medicine and researcher at the USF Health Byrd Alzheimer’s Institute, said that this is a very important pathological link for ALS and FTD.

“Mutations in the ALS and FTD gene, called CHCHD10, are instigating dysfunction in the mitochondria, the cell powerhouse plants that produce the majority of the energy in the human body,” Dr. Kang said. “This gene allows TDP-43, a protein that’s part of the nuclear function, to exit the nucleus to get into the cytoplasm or cell body and cause TDP 43-pathology – which is relatively specific to ALS and FTD.”

While many genes cause ALS and FTD, this gene is the first one that’s been linked to mitochondria, Dr. Kang said. Dr. Kang and his team of researchers have worked on this study for two years, supported by grants from the Veterans Administration, National Institutes of Health and Florida Department of Health.

Dr. Kang (second from right) with some members of his research team. From left: JungA (Alexa) Woo, PhD, assistant professor; Courtney Trotter, graduate research assistant; and Tian Lu, PhD, postdoctoral research scholar, Department of Molecular Medicine, USF Health Morsani College of Medicine.

To come up with the results, the USF Health researchers studied worms, mammalian cell lines, primary neurons and mouse brains. The models allowed them to prove that the mutated gene is very important to the mitochondrial function, which the human body needs.

“We took the human gene, CHCHD10, and we put it into worms with a short life-span,” Dr. Kang said. “We used worms who lacked the CHCHD10 gene and had dysfunctional mitochondria, which, as a result, had motor problems and could not move properly. What happened was that the normal human gene helped the worms live longer – completely rescuing their abnormalities and restoring their mitochondria function and movement. However, when we put the single mutated gene that causes ALS and FTD into the worm, it did not rescue at all. They were still completely dysfunctional.”

The USF Health research team suggests that these results are critical to ALS and FTD research. This was the first study to show that the normal gene increases mitochondria function and the mutant gene increases mitochondria dysfunction. The normal gene is bound to TDP-43 protein and allows it to stay in the nucleus.

Alexa Woo, PhD

However, when TDP-43 pathology is outside the nucleus, it decreases mitochondria function and synaptic integrity, connecting points between neurons. Researchers said synapse loss occurs in all neurodegenerative diseases.

This is an important step into the right direction, but researchers at USF Health agree that there is more work to be done.

“I think ultimately, if we can understand how the neurodegenerative disease leads to aberrations at the molecular level, then we can potentially target specific molecules that induce pathology in ALS or FTD,” Dr. Kang said.

Photos by V.  Hysenlika


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