With the sudden popularity of the ice bucket challenge this past summer, many people were introduced to the neurodegenerative disease known as amyotrophic lateral sclerosis (ALS). The goal of the challenge was to help fund research to find a cure for ALS, which is newly diagnosed at least 6,000 times per year and for which there currently exists no effective treatment.
Though a cure for the disease is far from complete, Hopkins research has helped identify a chemical that targets a protein present in many individuals affected with ALS. Scientists from the Mayo Clinic and the Scripps Research Institute discovered the chemical, whose name has not yet been released.
ALS is also known as Lou Gehrig’s disease, after the baseball player who was affected by the disease and made it well known around the U.S. It weakens neurons in the central and peripheral nervous systems, which eventually leads to loss of voluntary motor control and muscle weakness, and it is ultimately fatal due to respiratory failure.
ALS can have a tendency to run in families, suggesting that its cause can be linked to changes in the human genetic code. These changes can result in the transcription of radically different proteins, which may affect the way our cells function by binding to, altering, or disabling other proteins and organelles.
The Mayo Clinic and Scripps Research Institute scientists cited Hopkins research from three years ago that focused on a mutation in the C9ORF72 gene on the ninth human chromosome. In the healthy gene, a six-nucleotide DNA sequence, GGGGCC, is repeated no more than 30 times. Because of the relative shortness of the sequence, it can be spliced out easily during DNA transcription and therefore not affect the production of proteins. However, in as many as 40 percent of individuals affected with ALS, the six-letter sequence repeats at least a thousand times. This leads to the transcription of excess “junk” messenger RNA (mRNA) and increases production of a protein known as C9RAN.
While the exact function of C9RAN is unknown, some have hypothesized that large amounts of the protein can clump around neurons. Similar clumping of other proteins has long been linked to neural degeneration. Indeed, the Hopkins researchers discovered abnormally high concentrations of C9RAN in the spinal fluid of many ALS patients.
The researchers suspect that the excess protein had “spilled out” from affected nerve cells.
The newly discovered chemical was shown to reduce production of the C9RAN protein by as much as half in nerve cells with the C9ORF72 mutation. This suggests that it may interact with the excess nucleotides in DNA and mRNA, silencing some of the repeats and resulting in less translated protein.
The mutation has also been linked to frontotemporal dementia (FTD), a condition that results in similar degeneration of neurons in the frontal and temporal lobes of the brain. FTD is one of the most common forms of dementia, second only to Alzheimer’s disease.
These results have profound implications for drug therapies that are currently being developed to treat these neurodegenerative diseases. However, like with any other new drug, further testing is required before clinical trials on patients can be approved.
For now, the researchers will have to trust that their chemical is good at what they have shown it to do. But with so much unknown about the causes and possible treatments for ALS, it may be a while before we can truly understand the potential of this chemical as a plausible cure.
