Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing in GGC repeat disorders

Area of Science:

• Neurobiology
• Molecular Biology
• Genetics

Background:

• Expanded GGC repeats lead to aggregation-prone polyglycine proteins implicated in neurodegenerative disorders.
• Polyglycine aggregates are a hallmark of several emerging neurological conditions.

Purpose of the Study:

• To investigate the molecular mechanisms by which polyglycine aggregates contribute to neurodegeneration.
• To explore the link between polyglycine aggregation, FAM98B, and transfer RNA (tRNA) processing defects.

Main Methods:

• Biochemical assays to study protein aggregation and interactions.
• Analysis of patient tissues for protein depletion and aberrant tRNA intermediates.
• In vivo studies using mouse models with Fam98b depletion.

Main Results:

• Polyglycine forms aggregates that sequester endogenous glycine-rich proteins, notably FAM98B, a key component of the tRNA ligase complex (tRNA-LC).
• Sequestration of FAM98B disrupts tRNA processing, leading to accumulation of aberrant tRNA splicing intermediates observed in patient tissues.
• Fam98b depletion in mice results in progressive motor deficits and hindbrain pathology.

Conclusions:

• The glycine-rich intrinsically disordered region (IDR) of FAM98B is a critical link between polyglycine aggregation and tRNA processing disruption.
• These findings mechanistically connect previously distinct neurodegenerative disorders characterized by protein aggregation and tRNA processing defects.
• FAM98B's role in tRNA processing is crucial for maintaining motor function and preventing neurodegeneration.