298 Loss of Proteostasis as a Pathomechanism in Premature Aging Disease Trichothiodystrophy

Abstract

The term, trichothiodystrophy (TTD) was first coined by Price et al in 1980 to describe patients with sulphur deficient brittle hair, which was then later characterized as a marker for this complex disease. TTD is a rare autosomal recessive, multisystem disease in which every organ of the body may be affected in particular the neuroectodermal tissues. Symptoms in particular ranging from delayed development, intellectual disability and cachexia to recurrent infections are manifested at an early age characterizing it as a progeroid syndrome. Approximately half of the patients with TTD suffer from a photosensitive form which is caused by mutations in three subunits (XPB, XPD and TTDA) of the basal transcription factor TFIIH. TFIIH is a multiprotein complex playing an essential role in initiation of transcription by RNA polymerases I and II and Nucleotide Excision Repair NER. TTD also serves as a disease model for accelerated ageing and its study could help in understanding physiological ageing. Preliminary data of our study on TTD cells show that the patients suffer from disturbed RNA polymerase I transcription which further leads to disturbed ribosomal biogenesis. Further disturbance in the quality of ribosomes is indicated by the reduction in 18S rRNA along with reduced translational fidelity. Inaccurate translation leads to the increased amount of misfolded proteins which activates the Unfolded Protein Response (UPR) of a disturbed proteome. In return UPR represses RNA polymerase I transcription. Moreover in our study we also show that the use of chemical chaperones like TUDCA (tauroursodeoxycholic acid) can rescue ER stress thus restoring the disturbed RNA polymerase I transcription. These findings can overall help us in understanding the pathomechanism and also in implying possible treatments for this severe premature aging syndrome.