A groundbreaking study has identified two proteins that interact with a mutant FUS variant linked to familial amyotrophic lateral sclerosis (ALS), offering a potential therapeutic target. Researchers found that inhibiting these proteins in motor neurons derived from human stem cells reduced ALS-related changes, suggesting similar mechanisms may be involved in sporadic ALS.
Key Takeaways
- Inhibiting PARP1 and reducing H1.2 levels in motor neurons reduced ALS-related neurodegeneration.
- Experiments in C. elegans showed decreased FUS aggregation when these proteins were knocked down.
- Findings suggest potential relevance to sporadic ALS, which accounts for 90% of cases.
The Study and Its Findings
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective degeneration of upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. The cause of ALS remains unknown in 90 percent of cases, referred to as sporadic ALS, which have no family history. The remaining 10 percent of ALS cases are hereditary and linked to mutations in over 30 distinct genes involved in different cellular processes.
Professor Dr. David Vilchez and his team at the University of Cologne’s CECAD Cluster of Excellence for Aging Research identified two proteins interacting with an ALS-causing mutant FUS variant (FUS P525L) by investigating motor neurons derived from human induced pluripotent stem cells (iPSC). Their results indicate that inhibiting those interacting proteins could be a possible therapeutic target for familial cases caused by mutations in FUS.
The Proteins Involved
The two proteins which interacted with the mutant FUS protein were PARP1, an enzyme promoting poly ADP-ribosylation (PARylation), and histone H1.2, a protein involved in wrapping the cells’ DNA in their known shape of chromosomes. In further experiments in human motor neuron cells, the researchers found that inhibiting PARylation or reducing H1.2 levels alleviates ALS-related changes such as the aggregation of mutant FUS protein and neurodegeneration.
Experiments and Implications
Next, the scientists conducted experiments using the nematode Caenorhabditis elegans as a model of ALS. They found that when the worms’ orthologs of the human proteins PARP1 and H1.2 were knocked down, the aggregation of mutant FUS and neurodegeneration also decreased. The scientists also observed that ALS-related changes worsen when these two proteins were overexpressed in C. elegans.
“Considering all our data, our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications,” said Dr. Hafiza Alirzayeva, first author of the study.
Future Research Directions
According to the researchers, the pathology between familial ALS, on which this study focused, and sporadic ALS is very similar. Although FUS is mutated in certain familial cases, non-mutant FUS aggregates in many sporadic cases as well. Professor Dr. David Vilchez, Principal Investigator at CECAD, said, “Most basic research focuses on the mutant genes that cause familial ALS because at least we know those genes. But we hope to show in further studies that our findings could have a potential impact on sporadic ALS as well, since that is the form that affects the overwhelming majority of patients.”
In future work, the authors will study whether these proteins could also be involved in ALS-related changes associated with other genes that cause the disease such as TDP-43 and C9orf72, as well as those of sporadic ALS.
Sources
- Two New Proteins Linked to ALS – Neuroscience News, Neuroscience News.
