Fen-Biao Gao, PhD
Research at UMass Medical School found that age-related DNA damage caused by oxidative stress is a key contributor to the breakdown of motor neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia patients (FTD) with hexanucleotide repeat expansions in the C9ORF72 gene, the most common genetic cause of both diseases. Details of the study, led by Fen-Biao Gao, PhD, were published in the journal Neuron and identify a molecular pathway that damages DNA through mitochondrial dysfunction that scientists hope they can target for treatment for these diseases.
“Understanding how these mutations lead to motor neuron damage is important to the development of new treatment approaches,” said Dr. Gao, professor of neurology. “Patients with this mutation produce abnormal proteins that hamper mitochondrial function and increases oxidative stress in their neurons. Finding a way to potentially reduce that oxidative stress or boost mitochondrial function in motor neurons may help patients with these diseases.”
In ALS, a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system, the C9ORF72 gene accounts for 40 percent of inherited forms of the disease and 6 percent of sporadic cases. As motor neurons die, the brain’s ability to send signals to the body’s muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually death from respiratory failure.
Similarly, FTD, originally called Pick’s disease, is the second most common form of early-onset dementia, behind only Alzheimer’s disease. FTD is caused by the loss of neurons in the frontal or temporal lobes.
Progress has been made in identifying genetic mutations that cause ALS and FTD, but how these changes affect neurons and cause toxicity is still poorly understood. Patients with the C9ORF72 mutation have an abnormally long GGGGCC repeat expansion in the gene. This expansion is responsible for the production of several unintended proteins called dipeptide repeat (DPR) proteins—ones not normally found in healthy people—that are in fact toxic to motor neurons, according to Gao and colleagues.
They also found that these DPR proteins physically interacted with more than 200 proteins and many of them are RNA binding proteins such as mitochondrial ribosomal proteins. DPR proteins interfered with normal functioning of mitochondria, which are responsible for generating most of the cell’s energy supply. This interference likely led to an increase in oxidative stress, which led to damage to DNA. Reducing the oxidative stress, according to the findings from Gao’s team, reduced the DNA damage.
“Because we used induced pluripotent stem cells from patients with ALS and FTD in this study to show that C9ORF72 toxicity can be suppressed in cultures, this experimental system is also good for potentially screening for potential therapeutic drugs,” said Gao.