Study reveals new gene involved in motor neuron diseases

According to a new study from an international research team, co-directed by Scripps Research molecular biologist Claudio Joazeiro, PhD, failures in a quality control system that defends protein-building fidelity in cells can result in motor neuron degeneration and associated diseases.

Claudio Joazeiro, PhD, is a professor in the Scripps Research Department of Molecular Medicine. Image Credit: Scripps Research Institute.

Motor neurons regulate breathing, movement, speaking, and swallowing activities. Their death is a feature of progressive diseases, like ALS, also called Lou Gehrig's disease, and spinal muscular atrophy.

Interpreting the factors responsible for destroying the motor neurons is crucial for developing precision treatments. Investigators have found that there are many causes of motor neuron diseases.

The study was published in the Nature Communications journal on September 15^th, 2020. It pinpointed many variants of a gene known as NEMF as a new driver of motor neuron disorders. Nuclear export mediator factor (NEMF) is known to play a role in clearing glitches that unavoidably take place during production of proteins by cellular organelles, known as ribosomes.

Healthy NEMF supports the cell to recycle the distorted fragments of proteins that are produced erroneously. However, the various mutant forms of NEMF in mice disrupted the system and led to neurodegenerative, neuromuscular or other disease, the researchers found.

The study was headed by both Joazeiro, who has joint appointments at Scripps Research in Jupiter, Florida and the Center for Molecular Biology of Heidelberg University in Germany, and also by Gregory Cox, PhD, from the Jackson Laboratory of Mammalian Genetics in Bar Harbor, Maine.

Ten years ago, Joazeiro identified an enzyme, called the E3 ubiquitin ligase listerin/Ltn1, that functions in a specialized quality control process currently called ribosome-associated quality control (RQC).

Joazeiro and his group also discovered that inactivation of the enzyme leads to motor neuron degeneration in mice.

But whether neurodegeneration emerged from defective ribosome-related quality control or some other function of listerin is still vague. At the Jackson Laboratory, Cox has been examining mice with mutations in another quality control factor, called NEMF.

The mice displayed movement problems such as gripping and walking. The laboratories joined together to examine whether such defects resulted from a neurodegenerative process. The team wanted to identify the molecular mechanisms at work.

The results provide strong evidence that dysfunction of ribosomal quality control causes neurodegeneration.”

Claudio Joazeiro, PhD, Professor and Molecular Biologist, Department of Molecular Medicine, Scripps Research Institute

Millions of ribosomes within the cells change genetic code into proteins by stringing together a single amino acid at a time. Sometimes, errors take place, a few of which result in the production of possibly toxic protein fragments. When that occurs, manufacturing may be stopped, and the cell’s ribosome protein quality control system destroys the disordered parts for recycling.

However, whether defective ribosome quality control played a role in human disease had remained elusive, to date. Human data supported the yeast- and mouse-based research of the team.

Working through GeneMatcher, a tool meant for patients and developed at the Baylor-Hopkins Center for Mendelian Genomics in Texas, the researchers identified nine patients from seven unrelated families who probably had pathogenic NEMF variants and exhibited neuromuscular disease, together with a range of developmental issues such as intellectual disability and speech delay.

It was amazing to see how our early and new mouse data, together with the knowledge acquired on molecular mechanisms, were so predictive of these findings in human patients. We're hopeful these advances will one day prove helpful to families affected by these difficult diseases.”

Claudio Joazeiro, PhD, Professor and Molecular Biologist, Department of Molecular Medicine, Scripps Research Institute

The researchers are now examining the role of ribosome-associated quality control in another associated diseases, he added.

Another interesting takeaway from this study is that this route of protein quality control seems to be needed throughout species, Joazeiro further added.

According to Joazeiro, “Last year we reported that it is also present in bacteria, and is likely to have already been active in the last universal common ancestor, the organism that gave rise to all domains of life.”

Along with the discoveries that deactivating the system leads to neurodegeneration, this evolutionary conservation emphasizes the significance of abnormal protein disposal, and also indicates that the development of the system may have played a vital role, allowing the evolution of complex organisms, added Joazeiro.

This research shows that failure of ribosome-associated quality control is a cause of motor neuron disease that should be explored in greater detail.”

Claudio Joazeiro, PhD, Professor and Molecular Biologist, Department of Molecular Medicine, Scripps Research Institute