DNA repair requires proteins both to carry out repairs and to recognize molecular signals associated with when and where repair is needed. Dr. Jean-François Couture, a full professor in the University of Ottawa Faculty of Medicine’s Department of Biochemistry, Microbiology and Immunology and the study’s co-corresponding author, said the work shows how changes that interfere with this recognition can compromise repair, threaten genome stability and ultimately contribute to disease. TONSL, a protein involved in maintaining genome integrity, emerged from the study as a central coordinator in this process.

The researchers found that TONSL interacts with H3.1 through several molecular binding pockets rather than through a single point of contact. Two pockets recognized specific modifications on the histone: methylation at one position and acetylation at another. These chemical marks are associated with DNA regions involved in regulating genes. Their results therefore indicate that DNA-repair recognition depends partly on the modification state of surrounding chromatin, including histone variants that can carry distinct molecular features recognized by other proteins. The binding pockets collectively allowed TONSL to interpret multiple signals associated with H3.1.

Human-cell experiments provided a disease-related test of this recognition mechanism. Mutations in a region of TONSL associated with sponastrime dysplasia weakened the protein’s ability to recognize H3.1, and the altered proteins failed to restore normal DNA repair function. Couture described this as evidence that the mutations disrupt the ability to coordinate repair machinery as cells prepare for division, allowing DNA damage to accumulate. The findings support a possible contribution of defective TONSL recognition to sponastrime dysplasia; they do not establish that the entire spectrum of the inherited skeletal disorder can be explained by this molecular defect.

The study builds on the team’s earlier work published in Science in 2022. Since then, new collaborations enabled the researchers to extend their analysis from isolated proteins to interactions involving living human and mammalian cells, providing a broader view of how TONSL and H3.1 behave in cellular systems. Dr. Hossein Davarinejad, the first author and a postdoctoral fellow in Couture’s laboratory, said the team next plans to investigate other proteins involved in DNA repair pathways and conduct structural studies of larger parts of the repair machinery. Overall, the experiments show that protecting genetic information involves more than executing repair: the repair system must also interpret the chemical features of chromatin to coordinate the response appropriately.

Subject of Research: Molecular recognition of histone H3.1 modifications by TONSL in DNA repair and genome stability

Article Title: Unravelling DNA repair: uOttawa-led team shows how cells protect their genetic blueprint

Article References: Unravelling DNA repair: uOttawa-led team shows how cells protect their genetic blueprint. Original publication (Bibliographic details unavailable.)

Image Credits: AI Generated

DOI: Not provided

Keywords: TONSL, DNA repair, histone H3.1, genome stability, chromatin, protein recognition, sponastrime dysplasia, cell division, University of Ottawa, Unravelling, repair, uOttawa-led

A team led by Dr. Derrick Gibbings, a professor in the Department of Cellular and Molecular Medicine at the University of Ottawa and a member of the Eric Poulin Centre for Neuromuscular Disease, has now reported a two-part strategy that addresses both halves of the problem: getting antibody drugs across the barrier, and making them actually destructive once they arrive. The work, led by research associate Huishan Guo in the Gibbings laboratory, was published in the journal Nature Biomedical Engineering on 26 August 2026 under the title “Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43.”

The delivery half of the solution relies on extracellular vesicles, tiny membrane-bound bubbles that cells naturally release into their surroundings. These vesicles ferry proteins, RNA and other cargo between cells as part of normal biology, and crucially, they have evolved ways of moving across the blood-brain barrier that synthetic drug carriers have not. The Ottawa researchers showed that extracellular vesicles can squeeze through the walls of blood vessels and enter the brain, carrying their molecular passengers with them. By loading therapeutic antibodies into or alongside these natural shuttles, the team found a way to dramatically raise the fraction of drug that reaches its target tissue, sidestepping the barrier that strands conventional antibody infusions in the blood.

Delivery alone, however, was never going to be enough. As Gibbings explains, antibodies raised against the pathological proteins behind Alzheimer’s disease, dementias and amyotrophic lateral sclerosis can bind their targets but cannot destroy them. “Normal antibodies can attach themselves to the disease-causing proteins in these diseases, but they can’t eliminate them and so aren’t as potent as they could be,” he says. In other words, a conventional antibody acts like a flag planted on a piece of debris, marking it for other systems to deal with, while the protein itself persists and continues to accumulate in the brain.

The second innovation therefore recruits one of the cell’s oldest housekeeping systems: autophagy. Often described as the body’s natural recycling plant, autophagy collects damaged or unwanted material inside the cell, engulfs it in a membrane sac and delivers it to the cellular machinery that breaks it down into small components the cell can reuse. The process is normally activated when cells are stressed or deprived of nutrients, and it is a fundamental mechanism by which cells clear their own molecular garbage. What the Ottawa team did was to hijack this disposal system and point it at the very proteins that drive neurodegeneration.

The researchers engineered antibodies that carry what the team describes as a baggage tag. When such an antibody binds a disease-causing protein, the tag recruits the autophagy machinery, directing the entire antibody-protein complex into the cell’s garbage disposal system for destruction. Rather than merely tagging pathological proteins and hoping something else clears them, these engineered molecules convert the immune recognition event into an active demolition order. The approach builds on a growing body of cell biology showing that autophagy receptors, the adaptor proteins that link cargo to the recycling machinery, can be repurposed to degrade specific targets on demand.

In cells and in mouse models, the strategy produced striking results. The team reported that engaging autophagy greatly improved the elimination of the proteins that cause Alzheimer’s disease, dementia and amyotrophic lateral sclerosis, and that the mice showed improvements in their disease symptoms. The pathological targets named in the published study, Tau and TDP-43, are two of the most notorious culprits in neurodegeneration. Tau tangles are a hallmark of Alzheimer’s disease and related dementias, while TDP-43 aggregates define the pathology of amyotrophic lateral sclerosis and frontotemporal dementia. A single platform capable of clearing both classes of proteins, and doing so through the cell’s own disposal route, represents a meaningful conceptual advance over approaches that only block or neutralize their targets.

The published work is described as a randomized controlled study performed in animals, and Gibbings is careful to frame it as a first step rather than a cure. Treating mice is one step, but an important one, on the road toward clinical trials and demonstrating benefits in patients, he notes. The history of neurodegenerative disease research is littered with therapies that looked powerful in animal models and failed to translate, which is precisely why the delivery component of this work may prove as consequential as the degradation component. A drug that cannot reach the brain cannot help the brain, no matter how elegant its mechanism.

There is nonetheless considerable momentum behind the underlying drug class. “There is a lot of enthusiasm for antibodies like these in industry, with many of the major pharma and biotech companies having invested billions of dollars in this space,” Gibbings says. “Many of these antibodies have been tried in patients in clinical trials but have shown minimal benefits to patients so far. We hope our new strategy to get these antibodies into the brain and eliminate their targets may be a key to making these drugs work for patients.” That framing captures the stakes: the molecules themselves are not new, but the combination of vesicle-based delivery and autophagy-directed destruction could finally give them the reach and the killing power they have lacked.

If the approach survives the long road to human testing, it could reshape how the field thinks about treating diseases of the central nervous system. Instead of designing ever-better antibodies and hoping a fraction of each dose crosses the barrier, researchers could pair existing recognition molecules with natural cellular transport systems and with the cell’s own recycling machinery. The Ottawa team’s results suggest that the barrier can be crossed, that pathological proteins can be actively destroyed rather than merely flagged, and that symptoms in animal models can improve as a result. For the millions of people living with ALS, Alzheimer’s, Parkinson’s and other dementias, that combination of delivery and destruction may be the key that turns decades of antibody investment into real therapeutic benefit.

Subject of Research: Engineered autophagy-recruiting antibodies delivered by extracellular vesicles to eliminate pathological Tau and TDP-43 in neurodegenerative disease models

Article Title: New drug-delivery method offers promise in fight against neurodegenerative diseases

Article References: New drug-delivery method offers promise in fight against neurodegenerative diseases. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: neurodegenerative diseases, extracellular vesicles, autophagy, blood-brain barrier, antibody drugs, Tau, TDP-43, ALS, Alzheimer's disease, University of Ottawa, drug-delivery, method

The study was led by Jessica Forrest, full professor in the Department of Biology at uOttawa’s Faculty of Science, with lead author Gil Miranda, a former postdoctoral researcher in her laboratory who is now with Agriculture and Agri-Food Canada. Over two summers, the team surveyed rural roadsides in neighbouring jurisdictions around Ottawa, Ontario, where different levels of government maintain vegetation under visibly different regimes. The work was funded through an NSERC Alliance grant and carried out in partnership with Agriculture and Agri-Food Canada and the Canadian Wildlife Federation, whose staff helped conceive and fund the study as part of its Rights-of-Way as Habitat program.

The comparison hinged on a natural experiment created by administrative boundaries. Lanark County mows its roadsides twice a year and spot-treats only invasive plants such as wild parsnip. The City of Ottawa and the United Counties of Leeds and Grenville, by contrast, mow up to four times a year and apply herbicide more broadly across the right-of-way. Because these jurisdictions sit side by side and share similar soils, climate, and surrounding farmland, the researchers could compare otherwise similar roadside sites and isolate the effect of management alone. The Canadian Wildlife Federation helped pinpoint site pairs that shared comparable surrounding landscapes but fell under different mowing regimes, strengthening the design.

The fieldwork was exhaustive. Miranda netted and identified 3,773 pollinator specimens across 31 sites, a collection that ultimately totaled 153 species: 100 bee species and 53 flower fly species. Species identifications were confirmed through DNA barcoding led by Sophie Cardinal of Agriculture and Agri-Food Canada, a step that matters enormously in pollinator research, where many species are morphologically similar and easily confused in the field. The numbers told a consistent story. Low-intensity roadsides averaged 27 species per site across the study, while conventionally managed roadsides averaged 22. Abundance followed the same pattern, with far more bees and flower flies recorded along the less intensively maintained corridors.

For Forrest, the magnitude of the effect was the striking part. “Roadsides aren’t places most people think of as wildlife habitat, but they add up to a huge amount of land across the country,” she explained. “What surprised us wasn’t that management mattered; it was how much difference two modest changes made.” The finding reframes roadside vegetation from a liability to be kept tidy into an asset that can be managed cheaply for biodiversity. In agricultural regions, where natural habitat has been largely converted to cropland, these unmowed strips may represent some of the last reliable patches of nesting substrate and forage available to wild bees and hoverflies.

The mechanism behind the result is straightforward ecology. Frequent mowing removes flowering plants before they can bloom, eliminating the nectar and pollen resources that adult pollinators depend on throughout the growing season. It also destroys nest sites for ground-nesting bees and can kill larvae developing in stems. Broad herbicide spraying compounds the damage by suppressing the very flowering forbs, including many native species, that pollinators feed on. Reducing mowing to twice a year allows a community of flowering plants to establish and complete their life cycles, while targeted spot treatment of invasive species such as wild parsnip controls problem plants without stripping out the rest of the vegetation community.

Importantly, the researchers are not arguing that roadsides should be abandoned altogether. “Roads still need to be safe to drive, and invasive species still need to be managed,” Forrest noted. “But our results suggest land managers don’t have to choose between that and supporting pollinators. Mowing less often and spraying herbicide only where it’s actually needed rather than across a whole roadside, gets you most of the way there.” Safety sightlines, drainage, and invasive plant control can all be preserved under a low-intensity regime; the key insight is that blanket maintenance across an entire right-of-way delivers little extra benefit for road safety while imposing a substantial cost on insect communities.

The timing of the findings could hardly be more relevant. Bee and flower fly populations face mounting pressure across North America, squeezed by habitat loss, pesticide exposure, disease, and climate change. A recent continental assessment found that more than one-fifth of native pollinator species are now at elevated risk of extinction. Pollinators underpin the reproduction of a large share of flowering plants and contribute substantially to the yields of many fruit, vegetable, and seed crops, so their decline carries consequences well beyond entomology. Against that backdrop, the Ottawa-area results offer what Forrest describes as a rare bit of good news: a low-cost intervention within reach of virtually any municipality or county that maintains rights-of-way.

That accessibility is arguably the study’s most powerful message. “You don’t need to plant anything new or spend more money to see a benefit,” Forrest concluded. “You just need to let the roadside be a little less tidy.” Unlike pollinator initiatives that require seed mixes, planting programs, or expensive restoration, the changes tested here are essentially cost-saving: fewer mowing passes mean less fuel, labour, and equipment wear, and precision spraying means less herbicide purchased and applied. The study, titled “Roadside pollinator populations and the negative impact of intensive roadside vegetation maintenance,” was authored by Gil Miranda, Tracey Etwell, Vincent Fyson, Sophie Cardinal, Carolyn Callaghan, and Jessica Forrest, and was conducted with the support and cooperation of the City of Ottawa, Lanark County, and the United Counties of Leeds and Grenville.

For the thousands of kilometres of rural road crisscrossing farmland and forest across Canada and the United States, the implications are hard to ignore. A modest revision to maintenance schedules and spray protocols, decided at the level of a county public works department, could convert an entire network of roadside strips into connected habitat threads running through otherwise intensively used landscapes. As researchers and conservation groups continue to search for scalable responses to pollinator decline, the Ottawa study suggests that one of the most effective tools available may already be parked in the municipal maintenance shed, waiting to be deployed a little less often.

Subject of Research: Effects of roadside vegetation maintenance intensity on pollinator abundance and diversity

Article Title: Mowing less, spraying smarter gives pollinators a boost

Article References: Mowing less, spraying smarter gives pollinators a boost. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: pollinators, roadsides, bees, flower flies, mowing, herbicide, biodiversity, habitat management, Insect Conservation and Diversity, University of Ottawa, conservation, rights-of-way