Summary: A new study identifies two proteins that interact with a mutant FUS variant linked to familial ALS, offering a potential therapeutic target. Researchers found that inhibiting these proteins in motor neurons derived from human stem cells reduced ALS-related changes.
The findings suggest that similar mechanisms may be involved in sporadic ALS, which affects most patients. Further research will explore these proteins’ roles in other ALS-related genes and sporadic cases.
Key Facts:
- 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.
Source: University of Cologne
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease which remains incurable. The disease is characterized by the selective degeneration of upper motor neurons in the motor cortex as well as the lower motor neurons in the brainstem and spinal cord.
The cause of ALS remains unknown in 90 percent of cases, which are referred to as sporadic ALS because there is no family history for the disease. Cumulative evidence suggests that sporadic ALS may result from complex interactions between genetic susceptibility and aging.
The remaining 10 percent of ALS cases are hereditary and linked to mutations in one of over 30 distinct genes involved in different cellular processes.
There are severe early-onset and juvenile cases, the majority of which are caused by mutations in the FUS gene. FUS is a protein widely expressed across tissues and has a role in various DNA and RNA processing steps, including DNA repair, transcription, RNA splicing, and nucleo-cytoplasmic RNA shuttling.
However, mutations in this protein particularly affect motor neurons in ALS.
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 study was published under the title ‘ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes’ in Cell Reports.
The two proteins which interacted with the mutant FUS protein were PARP1, an enzyme promoting poly ADP-ribosylation (PARylation), a modification that can alter proteins in different ways, and histone H1.2, a protein involved in wrapping the cells’ DNA in their known shape of chromosomes.
In further experiments in the 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.
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.
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.
About this ALS and genetics research news
Author: Eva Schissler
Source: University of Cologne
Contact: Eva Schissler – University of Cologne
Image: The image is credited to Neuroscience News
Original Research: Open access.
“ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes” by David Vilchez et al. Cell Reports
Abstract
ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes
Highlights
- ALS-related mutant FUS gains enhanced interaction with PARP1 in human motor neurons
- ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction
- Reducing PARylation and H1.2 levels attenuates ALS-related changes in motor neurons
- H1.2 and PARP1 also lead to mutant FUS aggregation in C. elegans
Summary
The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes.
Here, we define the interactome of the severe mutant FUSP525L variant in human induced pluripotent stem cell (iPSC)-derived motor neurons.
We find increased interaction of FUSP525L with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons.
Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUSP525L aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes.
Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.
