Vabilo na predavanje prof. Erika Storkebaum-a v sredo, 13. 3. 2024

Boris Rogelj | 12. 3. 2024

Pozdravljeni,

vabljeni na predavanje prof. Erik Storkebaum-a, Direktorja Donders centra za nevroznanost, Univerza Radboud, Nijmegen, Nizozemska, ki bo v sredo 13. 3. 2024 ob 11 h v seminarski sobi B220, na Institutu “Jožef štefan”.

V nadaljevanju posredujemo naslov in povzetek predavanja. Predavanje bo v angleščini. Več informacij o predavatelju najdete tukaj.

Lep pozdrav,

Boris Rogelj
Predsednik SiNAPSE

Prof. Dr. Boris Rogelj
Head of Department of Biotechnology, Jozef Stefan Institute
Professor at University of Ljubljana
President of Slovenian Neuroscience Society

boris.rogelj@ijs.si
http://www-b3.ijs.si/

Imbalance between tRNA supply and mRNA codon demand triggers peripheral neuropathy

mRNA translation by the ribosome involves decoding of mRNA triplet codons by tRNAs charged with the correct amino acid. Aminoacyl-tRNA synthetases mediate tRNA charging. For efficient mRNA translation, the cellular tRNA pool needs to be aligned with the mRNA codon demand. Heterozygous mutations in 7 cytoplasmic tRNA synthetases cause peripheral neuropathy. We recently reported that peripheral neuropathy associated with mutations in glycyl-tRNA synthetase (GlyRS) results in sequestration of tRNAGly by the mutant GlyRS, thus depleting the cellular tRNAGly pool under a critical threshold. This results in insufficient tRNAGly substrate for wild type GlyRS (derived from the wild type GARS allele in heterozygous patients), insufficient glycyl-tRNAGly production, and ribosome stalling on glycine codons. Ribosome stalling triggers GCN2-mediated activation of the integrated stress response (ISR) selectively in affected motor and sensory neurons. Consistent with this mechanism, transgenic tRNAGly overexpression rescues both inhibition of mRNA translation and peripheral neuropathy phenotypes and prevents ISR activation in Drosophila and mouse models of GlyRS-associated peripheral neuropathy. Therefore, elevating tRNAGly levels may constitute a novel therapeutic approach for GlyRS-associated peripheral neuropathy. Ongoing work revealed that tRNA sequestration also underlies peripheral neuropathy associated with mutations in tyrosyl-tRNA synthetase. Thus, identifying the molecular root cause of these forms of CMT uncovered elevating tRNA levels as a novel therapeutic approach.


© SiNAPSA 2003-2012