Summary: A new study identifies two proteins that interact with a mutant FUS variant implicated in familial amyotrophic lateral sclerosis (ALS), revealing a potential therapeutic target. Inhibiting these proteins in motor neurons derived from human induced pluripotent stem cells (iPSCs) reduced hallmark ALS changes, including mutant FUS aggregation and neurodegeneration.
The results suggest these mechanisms could also be relevant to sporadic ALS, which accounts for the majority of cases. Ongoing research will examine whether the same proteins contribute to pathological changes linked to other ALS-associated genes and to sporadic forms of the disease.
Key Facts:
- Inhibiting PARP1 activity and lowering histone H1.2 levels in human motor neurons reduced ALS-related neurodegeneration and mutant FUS aggregation.
- In a Caenorhabditis elegans model, knockdown of the worm orthologs of PARP1 and H1.2 decreased mutant FUS aggregation and neurodegeneration.
- Because non-mutant FUS also aggregates in many sporadic ALS cases, these findings may have broader relevance beyond familial FUS mutations.
Source: University of Cologne
Overview of ALS and FUS-related disease
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease marked by progressive loss of motor neurons in the motor cortex, brainstem, and spinal cord. Approximately 90 percent of ALS cases are sporadic, with no clear family history; these cases are thought to arise from complex interactions between genetic susceptibility and aging. The remaining 10 percent are familial and trace to mutations in more than 30 different genes.
Mutations in the FUS gene are responsible for many severe, early-onset and juvenile ALS cases. FUS encodes a multifunctional DNA- and RNA-binding protein involved in DNA repair, transcription, RNA splicing, and nucleo-cytoplasmic transport. Although FUS is expressed widely, its mutations disproportionately affect motor neurons, leading to rapid disease progression in affected patients.
Researchers led by Professor Dr. David Vilchez at the University of Cologne’s CECAD Cluster of Excellence used human iPSC-derived motor neurons to investigate how a severe FUS mutation, P525L, alters protein interactions. Their proteomic analysis revealed two key interacting partners: PARP1 and histone H1.2.
PARP1 is an enzyme that catalyzes poly-ADP-ribosylation (PARylation), a post-translational modification that can change protein function and interactions. Histone H1.2 is a chromatin-associated protein involved in organizing DNA within chromosomes. Both proteins showed enhanced interaction with the mutant FUS variant in motor neurons.
Functional experiments demonstrated that blocking PARylation or reducing H1.2 levels in human motor neurons attenuated several ALS-related phenotypes. These included decreased aggregation of mutant FUS, normalization of stress granule dynamics, and reduced apoptosis. Conversely, elevating H1.2 levels exacerbated FUS-related pathology, indicating H1.2 dose and interaction dynamics are important drivers of toxicity.
To test conservation of these effects in a whole-organism model, the team turned to Caenorhabditis elegans. Knocking down the worm orthologs of PARP1 and H1.2 reduced aggregation and neurodegeneration caused by mutant FUS, while overexpression of H1.2 increased toxicity. These cross-species results strengthen the evidence that PARylation and H1.2 interaction with FUS contribute directly to disease mechanisms.
Dr. Hafiza Alirzayeva, first author of the study, summarized the results by noting a clear link between PARylation, H1.2, and mutant FUS that may be exploitable for therapy. Professor Vilchez emphasized that although this work focused on familial FUS mutations, similar non-mutant FUS aggregation occurs in many sporadic ALS cases, so the findings could potentially inform treatments for the broader patient population.
Future studies planned by the team will investigate whether PARP1 and H1.2 contribute to pathological processes driven by other ALS-associated genes such as TDP-43 and C9orf72, and whether these mechanisms are active in sporadic ALS. If confirmed, targeting PARP1-mediated PARylation or modulating H1.2 levels could represent a new therapeutic strategy to slow motor neuron degeneration in ALS.
About this ALS and genetics research news
Author: Eva Schissler
Source: University of Cologne
Contact: Eva Schissler – University of Cologne
Image credit: Neuroscience News
Abstract
ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes
Highlights
- Mutant FUS (P525L) shows enhanced interaction with PARP1 in human motor neurons.
- ALS-FUS mutations promote abnormal PARylation and binding to histone H1.2.
- Inhibiting PARylation or lowering H1.2 levels reduces mutant FUS aggregation and neuronal death in human motor neurons.
- H1.2 and PARP1 orthologs also influence mutant FUS aggregation and neurodegeneration in C. elegans models.
Summary
Severe early-onset and juvenile ALS cases are frequently linked to FUS mutations that accelerate disease progression. Mutant FUS accumulates in stress granules and disrupts ribonucleoprotein complex dynamics. By mapping the interactome of FUS P525L in human iPSC-derived motor neurons, the study identified increased binding to PARP1 and histone H1.2. Experimental reduction of PARylation or H1.2 levels mitigated stress granule abnormalities, mutant FUS aggregation, and apoptosis. In vivo C. elegans experiments supported these findings, showing that knockdown of the corresponding orthologs reduces aggregation and neuronal loss, while H1.2 overexpression worsens phenotypes. Together, the data reveal a potential therapeutic axis linking PARylation, H1.2, and FUS in ALS.