Neurodegenerative GGC repeat expansions disrupt tRNA processing by aggregation of a singularly glycine-rich disordered area in FAM98B. In regular tRNA splicing, exons are ligated by the tRNA ligase advanced, a heteropentameric advanced containing FAM98B. PolyGly proteins produced in GGC repeat issues work together with FAM98B, which harbors the one most glycine-rich sequence within the human proteome, leading to sequestration and depletion of the tRNA ligase advanced. Credit score: Science (2025). DOI: 10.1126/science.ado2403
Raghu R. Chivukula, MD, Ph.D., a physician-investigator within the Departments of Medication & Surgical procedure and the Heart for Genomic Medication at Massachusetts Common Hospital and Harvard Medical Faculty, is the senior writer of a paper revealed in Science, titled “Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders.”
On this interview, he discusses his work.
How would you summarize your examine for a lay viewers?
Neurodegenerative issues, comparable to Alzheimer’s illness and Parkinson’s illness, are devastating and incurable illnesses. Though many neurodegenerative illnesses are characterised by irregular protein aggregation within the mind, a restricted understanding of whether or not and the way aggregated proteins trigger mind cell dysfunction and dying represents a serious barrier to creating efficient therapies.
Impressed by comparable approaches in heart problems and most cancers, we targeted on uncommon genetic types of neurodegeneration as a robust option to uncover elementary mechanisms tying protein aggregation to mind illness. Our work unexpectedly linked protein aggregation in genetic types of neurodegeneration to disrupted processing of switch RNAs (tRNAs), revealing an necessary mechanism that is perhaps therapeutically focused in these issues.
What query had been you investigating?
We grew to become fascinated with genetic types of neurodegeneration attributable to GGC trinucleotide repeat expansions (DNA sequence mutations attributable to copying this 3-letter sequence too many occasions in a row). These mutations produce aggregation-prone proteins with lengthy stretches of a single repeated amino acid (glycine). Curiously, though these “polyglycine”-containing protein aggregates are detectable in lots of tissue and cell sorts of affected sufferers, GGC repeat enlargement issues appear to trigger illness solely within the central nervous system.
We needed to grasp precisely what polyglycine aggregates do to cells and why they’re selectively poisonous to cells within the mind.
Which strategies or method did you employ?
We employed a biochemistry-based method to supply polyglycine proteins in cultured cells and to purify the resultant protein aggregates. Then we used mass spectrometry, which measures the quantities of various molecules in a pattern, to comprehensively catalog the set of host cell proteins which can be recruited into these aggregates and thereby depleted from cells.
We went on to check the results of polyglycine aggregation on RNA processing in cultured cells, confirmed our leads to human illness tissue samples, and developed mouse fashions to functionally assess the results of tRNA processing defects within the mind.
What did you discover?
We found that polyglycine aggregates, each in cultured cells and in human sufferers, particularly recruit the tRNA ligase advanced (tRNA-LC), a bunch of proteins which is required for processing spliced tRNAs. Notably, mutations in different tRNA splicing genes additionally trigger early-onset neurodegenerative illnesses much like GGC repeat enlargement issues. We discovered that aggregation of the tRNA-LC results in misprocessed tRNAs in cultured cells in addition to affected person mind samples.
Furthermore, mice by which we depleted the tRNA-LC within the mind developed neurodegeneration and motor coordination deficits much like these seen in GGC repeat issues.
What are the implications?
Our work reveals a brand new and sudden hyperlink between protein aggregation and RNA processing issues in GGC repeat illnesses.
The placing similarities between GGC repeat issues and beforehand described tRNA splicing issues counsel that polyglycine-dependent tRNA splicing disruption could also be an necessary mechanism underlying selective neuronal dying. Importantly, our findings additionally set up proof-of-concept that interfering with tRNA-LC aggregation could defend cells from the pathogenic results of GGC repeat expansions.
What are the following steps?
Our laboratory is now actively working to grasp the mobile and molecular penalties in vivo of altered tRNA splicing within the mind. We’re very fascinated with creating therapeutic methods that may block this pathogenic mechanism in neurodegenerative GGC repeat issues.
Extra info:
Jason Yang et al, Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat issues, Science (2025). DOI: 10.1126/science.ado2403
Supplied by
Howard Hughes Medical Institute
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Q&A: Researcher discusses the sudden position of protein aggregates in mind illness (2025, July 17)
retrieved 18 July 2025
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