Why do some genetic mutations devastate specific tissues while sparing others?. We explore this question in GGC repeat disorders, revealing a mechanism linking protein aggregation to tRNA splicing failure in the brain. 🧵 on our new paper in Science:.🔗

RT @DKThomp: One lesson of DOGE is that a lot of federal govt spending is sent to old ppl (social security, Medicare) and affluent individu….

RT @WalterWChen1: Our paper on discovering a new paradigm in peroxisome biogenesis and PEX39 (1st human peroxisomal biogenesis protein fou….

RT @YH_YukiBio: Excited to share our new preprint on @biorxivpreprint from our great team @EMBL!. If the nucleolus….

RT @rbarbosa91: Practicing knot tying is underemphasized in the training of those in non-surgical specialties. Many years of observation h….

RT @LukeKoblan: Excited to announce that this work is now live as a first release article @ScienceMagazine So grateful for this fantatic te….

RT @ImranSHaque: I find trinucleotide repeat disorders fascinating; between this new paper from @chivukula_raghu on GGC repeats and one ear….

RT @CellCellPress: Now online! SPIDR enables multiplexed mapping of RNA-protein interactions and uncovers a mechanism for selective transl….

Finally, we are grateful to funders including @BWFUND,.@ChenInstitute, Smith Family Foundation,.@MassGenBrigham, @MGHMedicine, @MGHSurgery, @CGM_MGH for supporting our work!. Thanks for reading!.🔗

This work was led by @jason_yang0 (now @BrunetLab) and aided by a talented and hardworking team: Forrest Xu, David Ziehr, @DrMartyTaylor @mlvalenstein @genfren Jack Bush, Kate Rutter, Igor Stevanovski, @CharlieYShi Mahesh Kesavan, @RMouroPinto @IDeveson David Bartel @DMSabatini.

We believe selective vulnerability reflects cell type–specific demands on molecular systems like RNA processing, translation, proteostasis, and secretion, among others. Want to learn more?. 🚨 Postdoc openings now available.📍 MGH / HMS / Broad.📩 rchivukula@mgh.harvard.edu.

This is our lab’s first major paper, and highlights a central question we are passionate about: Why do mutations affect some cells but not others?. We’re building a team to explore tissue-selective mechanisms in genetic disease—and we’re hiring!.

These findings unexpectedly bridge two previously distinct concepts:.- Neurodegeneration via protein aggregation.- Neurodevelopmental disease via tRNA processing defects. And, they suggest a possible therapeutic angle: Could restoring tRNA splicing help treat GGC repeat diseases?

Finally, we wanted to ask whether tRNA-LC depletion causally contributes to neuropathology. Indeed, depleting Fam98b in mice causes tRNA splicing defects, brainstem gliosis, cerebellar marker loss, and progressive motor deficits -- all reminiscent of human GGC repeat disorders.

Are these mechanisms relevant to human disease?. First, Mendelian tRNA splicing defects underlie neurodegenerative diseases that share many features with GGC repeat disorders. And, in GGC repeat patient tissues, we found tRNA-LC sequestration and tRNA exon accumulation!

Without FAM98B, splicing of intron-containing tRNAs fails. We observed accumulation of unligated tRNA exons upon polyGly expression and showed that this splicing defect is attributable to tRNA-LC depletion via the FAM98B Gly-rich IDR.

Notably, FAM98B is a key component of the tRNA ligase complex (tRNA-LC), essential for re-joining exons during tRNA splicing. We found that polyGly aggregates sequester and degrade the tRNA-LC from the soluble nucleoplasm via the FAM98B Gly-rich region.

We expressed synthetic polyGly proteins in human cells and purified the resulting aggregates. Unexpectedly, polyGly aggregates recruited other glycine-rich, intrinsically disordered proteins, with one clear standout: FAM98B, the most glycine-rich protein in the human proteome.

Both disorders produce aggregation-prone polyglycine (polyGly) containing proteins within intranuclear inclusions across the body. Nevertheless, symptoms are largely restricted to the nervous system. Is polyGly itself toxic? If so, how? And why selectively to the brain?

Many neurodegenerative diseases are marked by protein aggregates, but how those aggregates cause disease is often mysterious. GGC repeat disorders like FXTAS and NIID are prime examples—exhibiting nearly identical neurodegenerative phenotypes despite unrelated gene loci. How?.