September 23, 2019Neurology
Neurons, like other cells, constantly manufacture proteins, the cell's workhorses. Instructions for making proteins are encoded in chromosomal DNA and stored in the nucleus. Manufacturing starts when DNA instructions are transcribed into RNAs, which are packaged as granules and transported out of the nucleus to other parts of the cell for assembly. Unlike in other cells, RNA in neurons may have to travel over great distances - sometimes up to four feet - down stringy axons or through dendritic branches.
Amyotrophic lateral sclerosis (ALS), affecting at least 14,000 Americans, is a progressive, paralyzing and highly fatal neurodegenerative disorder for which there are no effective treatments. ALS is a group of rare neurological diseases that mainly involve the nerve cells (neurons) responsible for controlling voluntary muscle movement. Voluntary muscles produce movements like chewing, walking, and talking. Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease. ALS belongs to a wider group of disorders known as motor neuron diseases, which are caused by gradual deterioration (degeneration) and death of motor neurons. Motor neurons are nerve cells that extend from the brain to the spinal cord and to muscles throughout the body. These motor neurons initiate and provide vital communication links between the brain and the voluntary muscles. In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, and stop sending messages to the muscles. Unable to function, the muscles gradually weaken, start to twitch (called fasciculations), and waste away (atrophy). Eventually, the brain loses its ability to initiate and control voluntary movements.
Early symptoms of ALS usually include muscle weakness or stiffness. Gradually all muscles under voluntary control are affected, and individuals lose their strength and the ability to speak, eat, move, and even breathe. Most people with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first appear. However, about 10% of people with ALS survive for 10 or more years.
According to a study published in Cell (19 September 2019), it is now possible to peer inside neurons and watch the workings of annexin A11, a gene linked to a rare form of ALS. Results showed that neurons may normally use the gene to ship internal housekeeping instructions via a newly discovered hitchhiking system and that disease-causing mutations may tie up deliveries at the cell's loading docks. When using advanced live cell microscopy, the authors found that annexin A11 plays a role in this process by helping RNA granules hitch rides onto traveling lysosomes. Until recently, lysosomes were mainly viewed as garbage cans that roam around inside of cells cleaning up waste. These unexpected results suggest that lysosomes might moonlight as RNA transporters. The authors also found that disease-causing mutations in annexin A11 prevented hitchhiking, which, in turn, prevented RNA from being delivered to the far reaches of neurons. Many genetic studies have found that ALS is often caused by mutations in genes known to play roles in either RNA processing or the control of lysosomes. These results suggest that there is a link between these seemingly different processes and that understanding this type of hitchhiking in neurons may lead to new treatments for ALS.