Control of neuronal proteostasis by stress-induced transfer RNA fragments (?tiRNA?) as a common stress pathway across neurodegenerative disorders.

This application is for supplemental funding through PA-18-591 for the recently funded grant (1R01AG058476-01), entitled ?Dysfunction of the autophagy-lysosomal pathway as a common mechanism of neurodegeneration,? and the JPND project to support collaborative studies between Dr. Finkbeiner?s lab (Gladstone) and the JPND RNA NEURO consortium. The two groups propose to identify common mechanisms in neurodegenerative diseases. Studies proposed in Gladstone?s funded grant will determine if the major protein and organelle clearance pathways, including autophagy, proteasome and lysosomal activity, and the endocytic pathway are dysfunctional in human models of ALS, FTD, HD and PD and if the dysfunction may be linked to neurodegeneration in these diseases. These models consist of iPSCs from patients with familial forms of these diseases differentiated to the neurons (i-neurons) most vulnerable in the disorders. Gladstone is uniquely positioned to investigate the common and divergent mechanisms that impair the autophagy-lysosomal pathway (ALP) and protein clearance because the group developed a novel time-lapse imaging technology, robotic microscopy (RM), which is an unbiased, sensitive and quantitative method, to investigate perturbations in ALP and how those perturbations relate to neurodegeneration. They study ALP dynamics with a new technology, optical pulse-labelling (OPL), that quantitatively measures proteasomal and autophagic clearance pathways at a single-cell level. There is emerging evidence that protein translation and cellular proteostasis are controlled by small non-coding RNAs. ?Fine tuning? of protein translation by microRNAs is an established biological process that regulates multiple aspects of neuronal development, neurotransmission and neuronal function. New evidence described in the RNA NEURO grant proposal suggests that a distinct species of stress-induced, small non-coding RNAs derived from transfer RNA (?tiRNAs?) specifically regulate protein translation in response to cellular stress. tiRNAs promote stress granule (SG) formation and inhibit protein translation by displacing the translation initiation factor eIF4F from the ribosomal initiation complex, leading to a reduction in cap-dependent protein translation and stress resolution. Studies on the modulation of neuronal proteostasis by tiRNA are therefore of high relevance.

Award Date
23 August 2018
Award Value
Principal Investigator
Professor Jochen Prehn
Host Institution
Royal College of Surgeons in Ireland
Joint Programming Initiative in Neurodegenerative Diseases