mRNA Linked to ALS and Other Disorders Found at High Levels in Nerve Fibers, Study Reports
RNA molecules that are associated with genetic disorders characterized by damage to nerve fibers are found at higher-than-usual numbers in compartments of nerve cells, a new study reports.
The research, “The human motor neuron axonal transcriptome is enriched for transcripts related to mitochondrial function and microtubule-based axonal transport,” appeared in the journal Experimental Neurology.
Problems with messenger RNA (mRNA) transport and conversion to proteins in nerve fibers, or axons, have been associated with neurodegenerative disorders. mRNAs, molecules generated from DNA, have various tasks in nerve fibers, including their regeneration and growth from the cell body (another structure of neurons).
Aiming to find which specific mRNA molecules are transported and play an important role in nerve fiber function, researchers at the University of Miami Miller School of Medicine mapped the entire collection of mRNAs (the “transcriptome”) in motor neurons — cells that control muscle contraction — derived from human induced pluripotent stem cell (iPSCs) from three healthy volunteers.
This approach allowed the scientists to overcome a longstanding obstacle of studying nerve cells — that of acquiring them from a living person. “The use of human, stem-cell derived motor neurons provides a unique opportunity to investigate this process and its role in health and disease,” Mario Saporta, MD, PhD, the study’s senior author, said in a press release.
After finding which genes are essential for nerve cells, investigators then focused on what goes wrong in neuromuscular disorders. They evaluated potential differences in gene expression among different parts of the motor neuron — the nerve fiber (axon) and the somatodendritic compartment, which includes the cell body and dendrites, another type of nerve cell extension. (Gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)
They identified 1,000 genes with the highest average expression out of a total of more than 19,000 genes. Next, they found that 859 of these genes had similar expression in the two compartments, leaving nearly 150 distinct genes to further assess.
“We demonstrated that approximately 13 percent of total mRNA are enriched in the axonal compartment of human iPSC-derived motor neurons,” said Saporta, a professor of neurology and human genetics, and director of the Charcot-Marie-Tooth Association (CMTA) Center of Excellence at the Miller School. This result is in accordance with recent studies with rat and human neurons, he added.
Genes found to have higher expressions in nerve fibers were associated with cellular energy production, transport of molecules along the axon, and protein breakdown. Interestingly, several transcripts (mRNA molecules) related to human genetic disorders associated with axonal degeneration were identified.
“In summary, we mapped for the first time the human motor neuron axonal transcriptome and identified several [mRNAs] linked to human genetic axonopathies [axon diseases] as enriched in axons of motor neurons,” the researchers wrote.
“The identification of locally expressed mRNA in the axon of motor neurons is extremely important for the better understanding of normal axonal function and its role in neurological diseases,” Saporta said. This discovery “may [also] create a platform for drug discovery using those genes as therapeutic targets.”
These researchers are now looking at motor neurons derived from patients with inherited neuropathies (nerve damage) and comparing the mRNAs in their nerve fibers to neurons from healthy controls. They are also using human iPSC-derived motor neurons to develop screening platforms for drug development for genetic neuropathies.