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Fen-Biao Gao, PhD |
Scientists at the UMass Medical School have found abnormal protein production, not nuclear RNA foci, is a major source of toxicity in the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The study was published in the journal Neuron.
The most common genetic cause of ALS and FTD, and the first genetic link between the two diseases, is a mutation in the C9ORF72 gene. Patients with the disease-causing mutation have an excessive number of a six-nucleotide repeat (GGGGCC) in the gene. While a person with the normal gene may have as many as 30 of these repeats, the mutated form of the gene may have hundreds or even thousands.
In ALS, a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system, this mutation 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.
FTD, originally called Pick’s disease, is the among the most common forms of early-onset dementia, second only to Alzheimer’s disease. It is caused by the loss of neurons in the frontal or temporal lobes and as much as a 70 percent loss of spindle neurons.
Huge strides have been made in identifying genetic mutations that cause ALS and FTD, but how these changes affect neurons and cause toxicity is still poorly understood. Genetic mutations, such as C9ORF72, produce numerous abnormal molecules that could potentially be toxic to cells.
Fen-Biao Gao, PhD, professor of neurology, and Helene Tran, PhD, a postdoctoral fellow in the Gao lab, used specially designed fruit fly models with the C9ORF72 mutation to see if RNA transcribed from the mutated gene led to a potentially harmful accumulation of mutant RNA in the cell nucleus or production of lethal dipeptide repeat proteins.
To mimic the disease-causing process as closely as possible in Drosophila, Dr. Tran and Dr. Gao designed a C9ORF72 model immediately after the mutation was reported in 2011 with 160 of the hexanucleotide repeats flanked by the same DNA sequences that occur on either side of the GGGGCC expansion in patients. “This is the first animal model that expresses repeats in a molecular context similar to the genetic sequences found in people with these diseases,” said Gao.
Surprisingly, their work showed that abundant accumulation of RNA in the nucleus did not adversely affect global RNA processing or neuron survival. This analysis was carried out in collaboration with Zhiping Weng, PhD, professor of biochemistry & molecular pharmacology and director of the Program in Bioinformatics and Integrative Biology, and her graduate student Jill Moore. Their fly model was able to survive with increased levels of the mutant RNA in its nucleus and did not exhibit any disease phenotypes.
However, when Tran bred and kept their fly model at warmer temperatures, 29 degrees Celsius instead of 25, the flies began to exhibit modest toxic effects and a few died prematurely. Further analysis of these warm-environment flies revealed that the nuclear RNA levels remained consistent but the flies had started making more dipeptides.
“These results, coupled with other experiments, suggest that sense nuclear RNA foci do not appear to be a major source of toxicity in C9ORF72 related ALS and FTD. The cellular damage appears to be a result of the abnormal proteins harboring the dipeptide repeat,” said Gao.
Gao cautioned that while dipeptide repeat proteins may play a major role in ALS and FTD, it remains possible that some other repeat RNAs, such as antisense nuclear RNAs, might be responsible for some element of neurodegeneration. He also suggested that the repeat RNAs may leak out of the nucleus and get translated into toxic dipeptides in older individuals, accounting for the age-related onset of the disease.
Related link on UMassMedNow:
Researchers reveal how a common mutation causes neurodegenerative disease
