title: Drosha inclusions are new components of dipeptide-repeat protein aggregates in FTLD-TDP and ALS C9orf72 expansion cases.
abstract: Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are 2 neurodegenerative disorders that share clinical, genetic, and neuropathologic features. The presence of abnormal expansions of GGGGCC repeats (G4C2 repeats) in a noncoding region of the Chromosome 9 open reading frame 72 (C9orf72) gene is the major genetic cause of both FTLD and ALS. Transcribed G4C2 repeats can form nuclear RNA foci and recruit RNA-binding proteins, thereby inhibiting their normal function. Moreover, through a repeat-associated non-ATG translation mechanism, G4C2 repeats translation leads to dipeptide-repeat protein aggregation in the cytoplasm of neurons. Here, we identify Drosha protein as a new component of these dipeptide-repeat aggregates. In C9orf72 mutation cases of FTLD-TDP (c9FTLD-TDP) and ALS (c9ALS), but not in FTLD or ALS cases without C9orf72 mutation, Drosha is mislocalized to form neuronal cytoplasmic inclusions in the hippocampus, frontal cortex, and cerebellum. Further characterization of Drosha-positive neuronal cytoplasmic inclusions in the hippocampus, frontal cortex, and cerebellum revealed colocalization with p62 and ubiquilin-2, 2 pathognomonic signatures of c9FTLD-TDP and c9ALS cases; however, Drosha inclusions rarely colocalized with TDP-43 pathology. We conclude that Drosha may play a unique pathogenic role in the onset or progression of FTLD-TDP/ALS in patients with the C9orf72 mutation.
authors.affiliation: From the Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Porta
authors.forename: Linda K
authors.initials: LK
authors.lastname: Kwong
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000073885:C9orf72 Protein; D042622:DNA Repeat Expansion / Q000235:genetics*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D066329:Protein Aggregates / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics*; D057177:TDP-43 Proteinopathies / Q000235:genetics* / Q000473:pathology
chemical_list: D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D066329:Protein Aggregates; D011506:Proteins; C517918:DROSHA protein, human; D043244:Ribonuclease III