Repeat-Associated Non-AUG (RAN) translation is a cellular process where proteins are made from regions of the genetic code not normally used for this function. Imagine a factory assembly line that starts building a product only when it receives a specific “start” signal. In RAN translation, the machinery begins assembly without this signal, often in the wrong place, leading to unexpected and problematic products. This process is a known factor in several inherited neurological diseases.
Unconventional Protein Production
The cell’s protein-building machinery, the ribosome, operates under a strict set of rules. It reads a messenger RNA (mRNA) transcript, a copy of a gene’s instructions, and searches for a specific three-letter code, AUG, to begin translation. This AUG codon signals the starting point for assembling amino acids into a functional protein.
RAN translation breaks this rule by initiating protein synthesis without an AUG start codon. This allows the ribosome to begin reading the mRNA at unexpected locations, particularly in areas with repetitive genetic sequences. Because the ribosome can start without a fixed point, it can read the same faulty sequence in multiple ways, known as different “reading frames.”
This ability to read a sequence in several frames means a single mutated gene can produce a variety of different proteins not made in healthy individuals. For instance, a repeating sequence of “CAG” could be read as intended, or it could be shifted and read as “AGC” or “GCA.” Each reading results in a different string of amino acids, leading to multiple proteins from one genetic defect.
The Genetic Stutter Trigger
The primary trigger for RAN translation is a genetic mutation known as a nucleotide repeat expansion. This occurs when a short sequence of the genetic code is repeated an excessive number of times, much like a stutter in a document. For example, a normal gene might contain “CAGCAGCAG,” but in a person with a repeat expansion disorder, this could become “CAGCAGCAGCAGCAGCAG.”
While short, stable repeats are common and generally harmless within the human genome, an abnormally high number of these repeats can destabilize the gene. It is this excessive repetition that creates unusual structures in the mRNA molecule, which are thought to prompt the ribosome to begin translation improperly. These expansions can happen in various parts of a gene, including protein-coding and non-coding regions.
The length of the repeat often correlates with the onset and severity of disease. Once the number of repeats crosses a certain threshold, the unusual translation process is initiated. This discovery has revealed a more complex picture, blurring the lines between diseases once thought to be caused by toxic RNA versus toxic proteins.
The Role in Neurodegenerative Diseases
The proteins produced through RAN translation, called dipeptide repeat proteins (DPRs), are a factor in several neurodegenerative diseases. These proteins are structurally abnormal and sticky, causing them to clump together inside nerve cells in formations called aggregates. This accumulation disrupts cellular processes necessary for a neuron’s health and survival.
These toxic DPRs can interfere with the transport of materials within the cell, disrupt the machinery for disposing of cellular waste, and impair the function of the nucleolus. The presence of these aggregates and the disruption they cause places immense stress on neurons, which can lead to their death. This progressive loss of nerve cells is the hallmark of neurodegenerative conditions.
The most studied example is the G4C2 repeat expansion in the C9orf72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this case, RAN translation produces five different DPRs that accumulate in the brains of patients. Other disorders linked to this mechanism include myotonic dystrophy, Fragile X-associated tremor/ataxia syndrome (FXTAS), and several types of spinocerebellar ataxia.
Therapeutic Strategies and Research
Scientists are exploring strategies to counteract the harmful effects of RAN translation. A prominent approach involves the use of antisense oligonucleotides (ASOs), which are small, synthetic strands of nucleic acid that act like molecular patches. They bind to the faulty mRNA transcript containing the repeat expansion, blocking the ribosome from accessing it and preventing RAN translation.
Another area of research is the development of small-molecule drugs. These compounds recognize and bind to the unusual structures formed by the expanded repeat RNA. By attaching to these structures, the small molecules can prevent the ribosome from initiating translation or help the cell recognize the faulty RNA for degradation. This approach aims to stop the production of toxic DPRs at its source.
Researchers are also investigating ways to enhance the cell’s quality control systems to identify and clear out the toxic DPRs that are produced. Modulating pathways like autophagy, the cell’s recycling system, could help mitigate the damage caused by protein aggregation. These therapeutic avenues are in various stages of research and clinical trials.