Presenter of 1 Presentation
TAU-ASSOCIATED RIBOSOMAL ABNORMALITIES IMPAIR RNA TRANSLATION IN TAUOPATHIES.
Abstract
Aims
Identification of mechanisms by which tau promotes cellular dysfunction remains as a fundamental gap in the field. Our published data show that tau normally associates with ribosomes, but in pathological conditions, pathological tau shifts the translatome yielding a maladaptive response. However, the molecular mechanisms driving this effect remain unknown. Our aim was to define when and where tau associates with ribosomes in cognitively normal and Alzheimer’s disease brains, and how these interactions affect translation.
Methods
Human Alzheimer’s and age-matched non-demented control brains were subjected to enhanced cross-linking immunoprecipitation (eCLIP) sequencing using different antibodies to total and pathological tau. In vitro experiments were used to validate eCLIP results. Ribosome profiling was performed from the same human brain samples. Computational analyses to identify translation dynamics was performed.
Results
Tau associated robustly with RNA, many of which have not been previously reported. Early and late-stage AD tau-RNA complexes shifted from coding to non-coding sequences. The consensus sequences that associated with tau contain numerous splice sites and start codons. RNA-stabilizing species associated with tau in AD brains. Tau overexpression impaired RNA processing, transport, and translation in vitro. We also identified changes to ribosome dynamics using ribosome profiling. For example, the types of proteins translated in disease brains participate in different gene ontologies compared to controls. Ribosome profiles revealed that tau interferes with ribosome maturation, suggesting that this enriches maladaptive ribosomes.
Conclusions
Our data suggest that production and assembly of the translational machinery is inadequate, leading to a maladaptive response to tau pathology. Overcoming these deficits may confer functional benefits. Moreover, tau exerts devastating effects on RNA availability for translation. Therefore, tau-mediated maladaptive translation may be a pathogenic event, and efforts to rescue these effects are currently underway.