Drosha Inclusions Are New Components of Dipeptide-Repeat Protein Aggregates in FTLD-TDP and ALS C9orf72 Expansion Cases. Issue 4 (April 2015)

• Record Type: Journal Article
• Authors: Porta, Sílvia; Kwong, Linda K.; Trojanowski, John Q.; Lee, Virginia M.-Y.
• Is Part Of: Journal of neuropathology and experimental neurology. Volume 74:Issue 4(2015:Apr.)
• Publication Date: 2015-04
• Subjects: Neurology -- Diseases -- Periodicals; Neurology -- Diseases -- Physiopathology -- Periodicals; 616.8047
• DOI: 10.1097/NEN.0000000000000182
• Languages: English
• ISSNs: 0022-3069

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Abstract</title> <p>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 <italic>Chromosome 9 open reading frame 72</italic> (<italic>C9orf72</italic>) 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 <italic>C9orf72</italic> mutation cases of FTLD-TDP (c9FTLD-TDP) and ALS (c9ALS), but not in FTLD or ALS cases without <italic>C9orf72</italic> 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 <italic>C9orf72</italic> mutation.</p> </sec> </abstract>