Scientists have identified histone H1.2 and the enzyme PARP1 as promising targets for therapies aimed at reducing neurodegeneration associated with amyotrophic lateral sclerosis (ALS).
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder marked by the targeted deterioration of upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord. In 90 percent of ALS cases, the cause is unidentified, leading to the classification of these instances as sporadic ALS, which occur without a family history of the condition. Increasing evidence suggests that sporadic ALS might stem from intricate interactions between genetic predisposition and the aging process.
The other 10 percent of ALS cases are hereditary and are associated with mutations in more than 30 different genes that play roles in various cellular functions. Some forms of ALS have early onset, particularly juvenile cases, which are often caused by mutations in the FUS gene. FUS is a protein common in many tissues responsible for numerous DNA and RNA processing activities, including DNA repair, transcription, RNA splicing, and the transport of RNA between the nucleus and cytoplasm. However, mutations in FUS primarily hinder motor neurons in ALS.
Professor Dr. David Vilchez and his research team at the University of Cologne’s CECAD Cluster of Excellence for Aging Research have discovered two proteins interacting with the mutant variant of FUS known as FUS P525L by studying motor neurons sourced from human induced pluripotent stem cells (iPSC). Their findings suggest that targeting these interacting proteins could serve as a potential treatment approach for familial ALS linked to FUS mutations. The results were published in Cell Reports with the title ‘ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.’
The two proteins that interacted with the mutant FUS were PARP1, an enzyme responsible for a chemical process called poly ADP-ribosylation (PARylation), which can significantly modify proteins, and histone H1.2, which helps package DNA into its characteristic chromosome structure. Further investigations in human motor neuron cells revealed that blocking PARylation or lowering H1.2 levels helped reduce ALS-related effects, including mutant FUS protein aggregation and neurodegeneration.
Subsequently, the researchers utilized the nematode Caenorhabditis elegans as an ALS model. They discovered that decreasing the levels of the nematodes’ counterparts to human PARP1 and H1.2 led to a reduction in the build-up of mutant FUS and neurodegeneration. They also noted that overexpression of these two proteins in C. elegans exacerbated ALS-related features. “Our findings illustrate a connection between PARylation, H1.2, and FUS, which may have therapeutic implications,” stated Dr. Hafiza Alirzayeva, the lead author of the study.
According to the researchers, there are significant similarities in pathology between familial ALS, the focus of this study, and sporadic ALS. While FUS mutations are present in certain familial cases, aggregates of the normal FUS protein are also observed in many sporadic cases. Professor Dr. David Vilchez, Principal Investigator at CECAD, commented, “Much of the foundational research targets the mutant genes associated with familial ALS, as these are known. However, we aim to demonstrate through subsequent studies that these findings may also influence sporadic ALS, which impacts the majority of patients.”
Moving forward, the authors plan to investigate whether these proteins may also play roles in ALS-related changes linked to other implicated genes, such as TDP-43 and C9orf72, as well as those associated with sporadic ALS.
