Summary: Researchers have identified a newly discovered mechanism that may contribute to nerve cell loss in people with motor neuron disease (MND), amyotrophic lateral sclerosis (ALS), frontotemporal dementia and age-related neurological decline.

New discovery in DNA repair offers hope for slowing MND and dementia

Source: University of Sheffield

Scientists at the University of Sheffield have uncovered a mechanism that could slow progression of neurodegenerative conditions such as motor neuron disease (MND), certain forms of dementia and neurological decline linked to ageing.

Researchers from the Department of Molecular Biology and Biotechnology (MBB) and the Sheffield Institute for Translational Neuroscience (SITraN) investigated the C9orf72 gene, which contains a short hexanucleotide sequence. When this six‑nucleotide sequence expands and repeats abnormally, it is known to be a major genetic contributor to ALS and frontotemporal dementia. The team found that these expansions promote the formation of DNA–RNA hybrids, known as R‑loops, which make the genome vulnerable to breakage in neurons.

Under normal conditions, cells use a set of DNA repair proteins to detect and mend breaks in the genome. The study shows that products of the C9orf72 expansion over-activate autophagy, a cellular clearance pathway that normally removes misfolded or unwanted proteins. This over-activation can drive degradation of essential DNA repair proteins, undermining the cell’s ability to fix chromosomal breaks. As DNA repair capacity falls, neurons accumulate damage and are more likely to die — a key step in neurodegeneration.

The research team, led jointly by Professor Sherif El‑Khamisy (Department of MBB) and Professor Mimoun Azzouz (SITraN), demonstrated in cellular and mouse models that suppressing the runaway degradation process preserves DNA repair machinery and prevents neuronal death even when genomic damage is present. Using genetic approaches to reduce the excessive autophagy‑linked degradation, they were able to restore repair function enough that damaged cells survived.

“We were able to shut down the out‑of‑control degradation process, which runs down the cell’s ability to fix genomic breaks, using genetic techniques,” said Professor El‑Khamisy. “Even though the DNA remained damaged, the cells were able to cope and did not die. Discovering this mechanism and its consequence is a significant step toward developing new therapies for motor neuron disease and other neurodegenerative conditions.”

Professor El‑Khamisy added that additional research is necessary, but the newly described pathway may contribute to nerve cell death in Alzheimer’s disease, Parkinson’s disease and other conditions where genomic instability and impaired repair are implicated. “If we can modulate this degradation process, we can preserve the DNA repair toolkit and reduce the cell‑death pathology,” he said.

MND is a devastating and progressive neurological disease that leads to muscle paralysis and progressive difficulty with everyday functions. The severity and rapid progression of MND make the search for effective therapies urgent. The Sheffield discovery, based on rigorous studies in cells and animal models, outlines a potential therapeutic strategy: preserve DNA repair factors by tempering excessive autophagy‑linked degradation to protect neurons from degeneration.

Professor Mimoun Azzouz, an ERC Advanced Investigator at SITraN, commented: “This work addresses a major gap in our understanding of how neurons die in MND patients. Identifying molecular targets that preserve DNA repair machinery could change how we approach therapy development. I am proud of the collaborative effort, including the contributions of our PhD student Callum Walker, and we look forward to translating these findings toward new treatments.”

Source: Amy Pullan, University of Sheffield

Original research: Abstract for “C9orf72 expansion disrupts ATM‑mediated chromosomal break repair” by Callum Walker et al., published in Nature Neuroscience (online July 17, 2017). DOI: 10.1038/nn.4604

Abstract

Hexanucleotide repeat expansions in C9orf72 are the most common genetic cause of ALS and frontotemporal dementia, but the mechanisms driving neurodegeneration are not fully understood. This research reports elevated levels of DNA–RNA hybrids (R‑loops) and double‑strand breaks in rat neurons, human cells and spinal cord tissue from C9orf72 ALS patients. Accumulation of endogenous DNA damage coincides with defective ATM‑mediated DNA repair signaling and with protein‑linked DNA breaks. The study shows that defective ATM signaling stems from accumulation of the autophagy adaptor protein p62, which impairs ubiquitylation of histone H2A and perturbs ATM activation. Expression of C9orf72‑related RNA and toxic dipeptide repeats in mouse central nervous system increases double‑strand breaks, impairs ATM signaling and triggers neurodegeneration. These findings identify R‑loops, chromosomal breaks and deficient ATM‑mediated repair as pathological consequences of C9orf72 expansions and suggest that genomic instability contributes to C9orf72‑linked neurodegeneration.