This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Researchers at the University of Cambridge and the MRC Laboratory of Molecular Biology have discovered a previously unknown cellular defense system that protects the brain from abnormal glycogen accumulation, which is linked to severe neurological disorders. In a study published this week 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 mobilize 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," said senior author Professor 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 nonprotein tagging maintains tissue health and prevents toxic buildups in normal cells. "We are beginning to realize that ubiquitylation extends far beyond proteins.
It is exciting to see what new biological roles emerge in the future," said first author Matthew Yip, a 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.
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