BioProject

RNASeq raw reads for mutant and corrected samples at day 60. Whole-genome sequencing reads for C3 and M3 samples. More...

RNASeq raw reads for mutant and corrected samples at day 60. Whole-genome sequencing reads for C3 and M3 samples. These raw data was used to identify A to I RNA editing sites as described in the publication. Neurodegenerative disorders are defined by histopathological inclusions containing specific aggregation-prone proteins. Parkinsons disease (PD) and Dementia with Lewy bodies (DLB) are defined as synucleinopathies, since a-synuclein (a syn) aggregates are thought to comprise the major neuropathology. Genetics has strongly implicated the autophagic lysosomal pathway in PD and DLB pathogenesis, although it is unclear how dysfunction of general cellular clearance pathways result predominantly in a syn accumulation. We find that insoluble inclusions extracted from synucleinopathy patient material extend beyond a syn and are comprised of co-aggregates of RNA and diverse metastable proteins, most prominently NONO/SFPQ that regulate pre-mRNA and gene expression. Nuclear NONO/SFPQ aggregates induced aberrant adenosine to inosine (A I) RNA editing through perturbing ADAR expression. Hyper-edited RNA occurred mainly in human-specific Alu repeat regions of axon/synaptic transcripts, causing nuclear retention and reduced expression. This indicates that pathological inclusions extend beyond a syn to include diverse, metastable proteins, with downstream deleterious consequences on expression of essential neuronal survival proteins. Less...