ALS-causing gene mutations disrupt key protein machinery: Study
Results shed new light on molecular mechanisms that can contribute to disease
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- ALS-causing NEK1 gene mutations disrupt cellular protein production machinery.
- Truncated NEK1 protein accumulates in the nucleolus, impairing ribosome biogenesis.
- This disruption leads to cell death and motor dysfunction, suggesting a common ALS pathway.
Mutations in the NEK1 gene — a major genetic cause of amyotrophic lateral sclerosis (ALS) — can disrupt the molecular machinery that cells normally rely on to make new proteins, according to a new study.
The results shed new light on the molecular mechanisms by which certain mutations can contribute to ALS.
The study, “Nuclear condensates formed by truncated mutant NEK1s impede ribosomal RNA biogenesis and drive motor dysfunction,” was published in Nature Communications.
NEK1 gene provides instructions to make a protein of the same name
The causes of ALS are in most cases unknown, but in a fraction of cases, ALS is driven by genetic mutations. Within the last decade, mutations in the NEK1 gene have been shown to be a common genetic cause of ALS, accounting for up to 3% of all cases.
The NEK1 gene provides instructions to make a protein of the same name that is important for various biological functions, including helping cells to maintain their structure and repairing damaged DNA. Several ALS-causing NEK1 mutations are predicted to result in the production of a shorter, or truncated, version of the NEK1 protein.
However, the biological mechanisms by which truncated NEK1 proteins may damage cells to cause ALS remain obscure. To fill this knowledge gap, a team of scientists in China conducted a battery of biochemical tests.
Normally, the NEK1 protein is located in the cytoplasm, the liquid that fills most of the cell. But the researchers found that truncated versions of the protein will instead accumulate in the nucleus, the cellular compartment that houses all of a cell’s DNA.
More specifically, truncated NEK1 protein was shown to build up in part of the nucleus called the nucleolus. This specialized compartment is mainly responsible for making protein-making molecular machines called ribosomes.
“Our findings broaden the understanding of NEK1-related ALS [development] and suggest that RNA metabolism dysregulation is a common [disease-driving] pathway in ALS.
Ribosomes translate information from the messenger RNA, the intermediate molecule derived from DNA that is used as a template for protein production, to build proteins. As such, when ribosomes aren’t working correctly, cells aren’t able to properly make new proteins.
And that’s exactly what happens when truncated NEK1 protein gets into the nucleolus. In experiments in lab-grown human cells, the researchers found that the disease-driving protein forms clumps with other proteins in this compartment, effectively disrupting production of new, healthy ribosomes. This disruption was associated with reduced protein production and cell death.
Further experiments in animal models showed that the presence of truncating NEK1 mutations was linked to motor problems and shorter survival in fruit flies, and motor deficits and ribosomal problems in mice. Further work is needed to verify if this is also seen in samples from people with this genetic form of ALS, the researchers noted.
The scientists also highlighted that other ALS-causing mutations have also been shown to disrupt how cells process mRNA and RNA that make up ribosomes.
“In summary, we uncover that truncated forms of NEK1 derived from [certain] ALS-related NEK1 … mutations disrupt [ribosome production],” the scientists wrote. “Our findings broaden the understanding of NEK1-related ALS [development] and suggest that RNA metabolism dysregulation is a common [disease-driving] pathway in ALS.”
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