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The neuropathology associated with repeat expansions in the C9ORF72 gene

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Abstract

An abnormal expansion of a GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72) is the most common genetic abnormality in familial and sporadic FTLD and ALS and the cause in most families where both, FTLD and ALS, are inherited. Pathologically, C9ORF72 expansion cases show a combination of FTLD-TDP and classical ALS with abnormal accumulation of TDP-43 into neuronal and oligodendroglial inclusions consistently seen in the frontal and temporal cortex, hippocampus and pyramidal motor system. In addition, a highly specific feature in C9ORF72 expansion cases is the presence of ubiquitin and p62 positive, but TDP-43 negative neuronal cytoplasmic and intranuclear inclusions. These TDP-43 negative inclusions contain dipeptide-repeat (DPR) proteins generated by unconventional repeat-associated translation of C9ORF72 transcripts with the expanded repeats and are most abundant in the cerebellum, hippocampus and all neocortex regions. Another consistent pathological feature associated with the production of C9ORF72 transcripts with expanded repeats is the formation of nuclear RNA foci that are frequently observed in the frontal cortex, hippocampus and cerebellum. Here, we summarize the complexity and heterogeneity of the neuropathology associated with the C9ORF72 expansion. We discuss implications of the data to the current classification of FTLD and critically review current insights from clinico-pathological correlative studies regarding the fundamental questions as to what processes are required and sufficient to trigger neurodegeneration in C9ORF72 disease pathogenesis.

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Acknowledgments

This work was supported by grants from the German Helmholtz Association (VH-VI-510, and W2/3 program, MN), the German Federal Ministry of Education and Research (01GI0704, MN), the Canadian Institutes of Health Research (74580, IRM), the Pacific Alzheimer’s Research Foundation (C06-01, IRM).

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Correspondence to Manuela Neumann.

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Mackenzie, I.R.A., Frick, P. & Neumann, M. The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta Neuropathol 127, 347–357 (2014). https://doi.org/10.1007/s00401-013-1232-4

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