St. Jude Children’s Research Hospital scientists report they may have cracked the mystery surrounding the most common genetic cause of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, suggesting possible new approaches to diagnosis and treatment.

Their findings were published recently in the journal Molecular Cell.

About 35% of ALS cases are associated with mutations in the gene C9orf72, making it the most common genetic cause of ALS and another neurological disease, frontotemporal dementia (FTD). The mutation leads to a dramatic increase in the number of short repetitive DNA sequences and results in the formation of abnormal repetitive proteins of varying lengths. These proteins are referred to as dipeptide repeat polypeptides (DPRs) Two of the formed DPRs contain the amino acid arginine, and are particularly toxic to neurons.

Until now, key details about the molecular mechanisms involved were uncertain, a media release from St. Jude Children’s Research Hospital explains.

“We have identified the protein, nucleophosmin, as a site of DPR toxicity,” says corresponding author Richard Kriwacki, PhD, a member of the St. Jude Department of Structural Biology, in the release.

“We also show that DPR toxicity is exquisitely length dependent. In the future, DPR length may have prognostic value for people with a diagnosis of ALS.”

Typically, a segment of the C9orf72 gene is repeated 20 to 30 times or less. However, those with ALS and FTD have hundreds or even thousands of the repeats, which then cause the formation of DPRs. Previous research from Kriwacki and others reported that the toxic (arginine-containing) DPRs disrupt assembly and function of the nucleolus, the largest membrane-less organelle in cells. This study highlights how they disrupt nucleolar assembly. The study also shows that longer DPRs are dramatically more toxic to cells.

The nucleolus resides in the nucleus and is where the protein factories of cells (called ribosomes) are assembled. Unlike the nucleus, the nucleolus lacks a membrane. Membrane-less organelles like the nucleolus rely on a process called liquid-liquid phase separation to form and give cells flexibility to respond to changing conditions. The same process explains why oil forms droplets in water, the release continues.

In their study, Kriwacki and his colleagues showed the toxic DPRs disrupt cell function by tightly binding to key regions of nucleophosmin, displacing other binding partners that help maintain the nucleolus and ribosome assembly. The greater the concentration of toxic DPRs, the faster the membrane-less nucleolus is altered and dissolved.

DPRs bind and sequester nucleophosmin within large complexes, causing the nucleolus to partially dissolve. Researchers showed the toxic DPRs also disrupted cell function by binding and isolating a key component of ribosomes — ribosomal RNAs.

“The work also provides a new direction for thinking about possible therapies to target toxic DPRs and their sites of action in patient cells,” states first author Michael White, PhD, a postdoctoral fellow in Kriwacki’s laboratory, in the release.

“Success will take totally innovative approaches,” Kriwacki adds. “But at least now we know what needs to be targeted.”

[Source(s): St. Jude Children’s Research Hospital, Science Daily]