A newly published paper details what the researchers describe as a vicious cycle of toxic protein production set in motion by cellular stress. The University of Michigan-led research brings scientists one step closer to understanding the development of neurodegenerative disorders such as amyotrophic lateral sclerosis.

The work shows how a repeat element in the DNA of C9orf72, a gene associated with amyotrophic lateral sclerosis and frontotemporal dementia, is translated into a toxic protein in the face of viral infection, starvation, toxins or problems with misfolded proteins. It’s the latest study investigating repeat-associated non-AUG (RAN) translation in a host of neurological disorders that result from repeat mutations, including Huntington’s disease, ataxia and myotonic dystrophy.

RAN translation happens in the absence of an AUG start codon, in multiple reading frames, through an expanded repeat to produce homopolymeric or dipeptide-repeat-containing proteins (DPRs). The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The most common start codon is AUG.

Outside Stress Influences

[caption id=“attachment_93759” align=“alignleft” width=“300”]Working model for how a feed-forward loop activates RAN Working model for how a feed-forward loop activates RAN translation and cellular stress pathways.
Credit: Katelyn M. Green et al, CC-BY[/caption]

The paper’s first author, Katelyn Green, a U-M graduate student in cell and molecular biology, said that

“Stressed cells typically stop making proteins, but in this case the stress actually activates more toxic protein production, creating a loop that potentially drives neuronal death.”

The research addresses the most common cause of ALS, or Lou Gehrig’s disease, leading to about 10 percent of cases. ALS is the most common motor neuron disease.

The same repeat expansion mutation is also the most common genetic cause of frontotemporal dementia. Senior author Peter Todd, M.D., associate professor of neurology, added:

“This suggests that outside stressors might influence when people get neurodegenerative diseases, even when the patient has a genetic mutation. This may help explain when and why some people develop neurodegenerative diseases later in life."

The researchers also found the same vicious cycle occurring at a second repeat mutation that causes a related neurodegenerative disease, fragile x-associated tremor/ataxia syndrome (FXTAS), suggesting this mechanism may be applicable to other repeat mutation disorders.

The work was funded by grants from the VA BLRD, the NIH, the Packard Foundation, the Michigan Alzheimer’s Disease Center and Protein Folding Disease Initiative.

Katelyn M. Green, M. Rebecca Glineburg, Michael G. Kearse, Brittany N. Flores, Alexander E. Linsalata, Stephen J. Fedak, Aaron C. Goldstrohm, Sami J. Barmada & Peter K. Todd RAN translation at C9orf72-associated repeat expansions is selectively enhanced by the integrated stress response Nature Communications 8, Article number: 2005 (2017) doi:10.1038/s41467-017-02200-0

Top Image: Calsidyrose/Flickr

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