Study Suggests Link Between Protein Aggregation and tRNA Processing in Neurodegeneration

In a study recently published in Science, researchers from Mass General Brigham described how protein aggregation relates to disrupted RNA processing in genetic neurodegenerative diseases. Disorders such as Alzheimer’s and Parkinson’s show abnormal protein buildup in the brain, but the connection between these aggregates and brain cell damage remains unclear. Focusing on rare neurodegeneration caused by GGC trinucleotide repeat expansions, the team explored mechanisms linking protein aggregation to brain dysfunction. 

These GGC mutations produce proteins with long repeated glycine sequences, forming polyglycine aggregates. While such aggregates appear in many tissues, the diseases affect only the central nervous system. “We wanted to understand exactly what polyglycine aggregates do to cells and why they are selectively toxic to cells in the brain,” senior author Raghu Chivukla explained. 

They generated polyglycine proteins in cultured cells, purified the aggregates, and used mass spectrometry to identify host proteins that were recruited into these aggregates and thereby depleted from the cells. They studied effects on RNA processing in cells, confirmed findings in patient brain tissue, and developed mouse models to assess altered tRNA processing in vivo.

The study found that polyglycine aggregates recruit the tRNA ligase complex (tRNA-LC), which is essential for processing spliced tRNAs. Mutations in other tRNA splicing proteins cause neurodegenerative diseases with symptoms resembling GGC repeat disorders. The aggregation leads to misprocessed tRNAs in both cultured cells and patient brain samples. Mice lacking brain tRNA-LC developed neurodegeneration and motor problems similar to disease symptoms.

This work demonstrates a connection between protein aggregation and RNA processing disruption, suggesting that polyglycine-induced impairment of tRNA splicing may underlie selective neuron death. It also provides evidence that preventing tRNA-LC aggregation could protect cells. The researchers plan to further study the consequences of altered tRNA splicing in the brain and develop therapies targeting this mechanism in GGC-related neurodegenerative disorders.