Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers

摘要: Hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of frontotemporal dementia and motor neuron disease. One consequence mutation formation different potentially toxic polypeptides composed dipeptide repeats (DPR) (poly-GA, -GP, -GR, -PA, -PR) generated by repeat-associated non-ATG (RAN) translation. While previous studies focusing on poly-GA pathology have failed to detect any clinico-pathological correlations cases, recent data from animal cell culture models suggested that it may be only specific DPR species are when accumulated certain intracellular compartments. Therefore, we performed a systematic correlative analysis with counting actual numbers distinct types inclusion (neuronal cytoplasmic intranuclear inclusions, dystrophic neurites) for each protein relevant brain regions (premotor cortex, lower neurons) cohort 35 cases covering clinical spectrum those pure MND, mixed FTD/MND FTD. had similar pattern anatomical distribution, total amount inclusions varied remarkably (poly-GA > GP > GR > PR/PA), indicating RAN translation seems more effective sense than antisense transcripts. Importantly, exception moderate associations poly-GA-positive neurites degeneration frontal cortex burden disease onset, no relationship was identified other or phenotype. Biochemical revealed close correlation between insoluble visible while did not find evidence presence soluble species. Thus, overall our findings strongly argue against role aggregation as major exclusive pathomechanism pathogenesis. However, this does exclude might essential pathogenesis interplay consequences associated expansion.