Polyglycine Aggregates Disrupt Trna Splicing And Drive Neurodegeneration

Raghu R. Chivukula, MD, PhD, a physician-investigator successful nan Departments of Medicine & Surgery and nan Center for Genomic Medicine astatine Massachusetts General Hospital and Harvard Medical School, is nan elder writer of a insubstantial published in Science, "Polyglycine-mediated aggregation of FAM98B disrupts tRNA processing successful GGC repetition disorders."

Q: How would you summarize your study for a laic audience?

Neurodegenerative disorders, specified arsenic Alzheimer's illness and Parkinson's disease, are devastating and incurable diseases. Although galore neurodegenerative diseases are characterized by abnormal macromolecule aggregation successful nan brain, a constricted knowing of whether and really aggregated proteins origin encephalon compartment dysfunction and decease represents a awesome obstruction to processing effective treatments.

Inspired by akin approaches successful cardiovascular illness and cancer, we focused connected uncommon familial forms of neurodegeneration arsenic a powerful measurement to uncover basal mechanisms tying macromolecule aggregation to encephalon disease. Our activity unexpectedly linked macromolecule aggregation successful familial forms of neurodegeneration to disrupted processing of transportation RNAs (tRNAs), revealing an important system that mightiness beryllium therapeutically targeted successful these disorders.

Q: What mobility were you investigating?

We became willing successful familial forms of neurodegeneration caused by GGC trinucleotide repetition description s (DNA series mutations caused by copying this 3-letter series excessively galore times successful a row). These mutations nutrient aggregation-prone proteins pinch agelong stretches of a azygous repeated amino acerb (glycine). Interestingly, though these "polyglycine"-containing macromolecule aggregates are detectable successful galore insubstantial and compartment types of affected patients, GGC repetition description disorders look to origin illness only successful nan cardinal nervous system.

We wanted to understand precisely what polyglycine aggregates do to cells and why they are selectively toxic to cells successful nan brain.

Q: What methods aliases attack did you use?

We employed a biochemistry-based attack to nutrient polyglycine proteins successful cultured cells and to purify nan resultant macromolecule aggregates. Then we utilized wide spectrometry, which measures nan amounts of different molecules successful a sample, to comprehensively catalog nan group of big compartment proteins that are recruited into these aggregates and thereby depleted from cells.

We went connected to study nan consequences of polyglycine aggregation connected RNA processing successful cultured cells, confirmed our results successful quality illness tissues samples, and developed rodent models to functionally measure nan consequences of tRNA processing defects successful nan brain.

Q: What did you find?

We discovered that polyglycine aggregates, some successful cultured cells and successful quality patients, specifically enlistee nan tRNA ligase analyzable (tRNA-LC), a group of proteins which is required for processing spliced tRNAs. Notably, mutations successful different tRNA splicing genes besides origin early-onset neurodegenerative diseases akin to GGC repetition description disorders. We recovered that aggregation of nan tRNA-LC leads to misprocessed tRNAs successful cultured cells arsenic good arsenic diligent encephalon samples. Moreover, mice successful which we depleted nan tRNA-LC successful nan encephalon developed neurodegeneration and centrifugal coordination deficits akin to those seen successful GGC repetition disorders.

Q: What are nan implications?

Our activity reveals a caller and unexpected nexus betwixt macromolecule aggregation and RNA processing disorders successful GGC repetition diseases.

The striking similarities betwixt GGC repetition disorders and antecedently described tRNA splicing disorders suggests polyglycine-dependent tRNA splicing disruption whitethorn beryllium an important system underlying selective neuronal death. Importantly, our findings besides found proof-of-concept that interfering pinch tRNA-LC aggregation whitethorn protect cells from nan pathogenic effects of GGC repetition description s.

Q: What are nan adjacent steps?

Our laboratory is now actively moving to understand nan cellular and molecular consequences successful vivo of altered tRNA splicing successful nan brain. We are very willing successful processing therapeutic strategies that tin artifact this pathogenic system successful neurodegenerative GGC repetition disorders.