Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy

摘要: GGGGCC repeat expansions of C9ORF72 represent the most common genetic variant amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We others have proposed that RNA transcribed from sequence is toxic via sequestration RNA-binding factors. Both GGGGCC-repeat (sense) CCCCGG-repeat (antisense) molecules are detectable by fluorescence in situ hybridisation as foci, but their relative expression pattern within CNS contribution to disease has not been determined. Blinded examination biosamples ALS patients with a expansion showed antisense foci present at significantly higher frequency cerebellar Purkinje neurons motor neurons, whereas sense granule neurons. Consistent this, inclusions containing or derived dipeptide proteins were respectively. Immunohistochemistry UV-crosslinking studies share similar interactions SRSF2, hnRNP K, A1, ALYREF, H/F. Together these data suggest that, although might be expected equally shared protein binding partners, distinct patterns various neuronal populations could lead differences pathogenesis injury. Moreover which primary target pathology ALS, presence (χ2, p < 0.00001) p = 0.75) correlated mislocalisation TDP-43, hallmark neurodegeneration. This implications for translational approaches disease, furthermore interacting RNA-processing factors transcriptional activators responsible versus transcription novel therapeutic targets. Electronic supplementary material The online version this article (doi:10.1007/s00401-015-1429-9) contains material, available authorized users.