Submitted by Yan Pan on Tue, 15/09/2026 - 16:00
Cambridge researchers discover how a cellular enzyme tags and clears toxic sugar in the brain, offering new targets for rare neurological diseases.
Researchers at the University of Cambridge and the MRC Laboratory of Molecular Biology have discovered a previously unknown cellular defence system that protects the brain from abnormal glycogen accumulations, which are linked to severe neurological disorders.
In a study published today in Nature, Professor Felix Randow and colleagues showed that a protein called RNF213 plays a key role in identifying abnormal glycogen. RNF213 attaches a small molecular tag called ubiquitin directly to defective glycogen molecules. This tag acts like a "dispose of this" signal, triggering a cellular recycling process known as autophagy to sweep away and break down the damaged energy stores.
Glycogen is the main form in which cells store glucose for energy, Its complex, highly branched structure keeps it soluble while allowing cells to rapidly mobilise glucose when energy is needed. When cells assemble glycogen incorrectly, or when quality-control mechanisms fail, the sugar becomes poorly branched and settles into dense, insoluble clumps called polyglucosan bodies. Over time, these toxic deposits accumulate inside brain cells, causing irreversible tissue damage.
We discovered that RNF213 tags abnormal glycogen with ubiquitin for disposal. A few years ago, we found RNF213 ubiquitylates LPS on intracellular bacteria, marking them for destruction. It is remarkable to see the same enzyme fighting bacteria and policing glycogen.
Senior author Professor Felix Randow, Director of Research at the Department of Medicine at the University of Cambridge and Group Leader at the MRC Laboratory of Molecular Biology
The new findings reveal that ubiquitin, previously known mainly for regulating proteins, can directly label carbohydrates such as glycogen. This fundamental shift expands our understanding of how non-protein tagging maintains tissue health and prevents toxic build-ups in normal cells.
We are beginning to realise that ubiquitylation extends far beyond proteins. It is exciting to see what new biological roles emerge in the future.
First author Matthew Yip, Postdoc in the Protein and Nucleic Acid Chemistry Division of the MRC Laboratory of Molecular Biology
Understanding this cleanup pathway is crucial for addressing rare genetic disorders such as Lafora disease and Polyglucosan Body Myopathy. Lafora disease is a devastating, inherited neurological condition that typically begins in adolescence. It triggers progressively severe seizures, rapid cognitive decline, and loss of motor control, and is ultimately fatal.
First identified in 1911 by Spanish neurologist Gonzalo Rodríguez Lafora, the condition is characterised by the accumulation of abnormal, poorly branched glycogen in the brain, forming deposits known as Lafora bodies. Despite more than a century of medical awareness, the condition remains incurable, and existing options only manage symptoms.
The new study improves our understanding of how cells maintain healthy energy stores and opens new avenues for treating diseases caused by polyglucosan accumulation.
Reference
Yip, M., Naydenova, K., Otten, E. et al. Quality control of glycogen through direct ubiquitylation by RNF213. Nature (2026). https://www.nature.com/articles/s41586-026-11139-6
