Neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 is linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins

• Published in: Neuropathology and applied neurobiology Vol. 42; no. 3; pp. 242 - 254
• Main Authors: Davidson, Y., Robinson, A. C., Liu, X., Wu, D., Troakes, C., Rollinson, S., Masuda-Suzukake, M., Suzuki, G., Nonaka, T., Shi, J., Tian, J., Hamdalla, H., Ealing, J., Richardson, A., Jones, M., Pickering-Brown, S., Snowden, J. S., Hasegawa, M., Mann, D. M. A.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.04.2016; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Aged; C9orf72; C9orf72 Protein; dipeptide repeat proteins; Dipeptides; DNA Repeat Expansion; DNA-Binding Proteins - metabolism; Female; frontotemporal lobar degeneration; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - pathology; Humans; Immunohistochemistry; Inclusion Bodies - metabolism; Inclusion Bodies - pathology; Male; Middle Aged; Motor Neuron Disease - genetics; Motor Neuron Disease - pathology; motor neurone disease; Nerve Degeneration - genetics; Nerve Degeneration - pathology; Neurons - pathology; Original; Pathology; Proteins; Proteins - genetics; Spinal cord; TDP-43; dipeptide repeat proteins; TDP-43; motor neurone disease; frontotemporal lobar degeneration; C9orf72
• ISSN: 0305-1846; 1365-2990
• DOI: 10.1111/nan.12292

Aims A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain. Methods Using antibodies to poly‐GA, poly‐GP, poly‐GR, poly‐AP and poly‐PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). Results Antibodies to poly‐GA, poly‐GP and poly‐GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as ‘star‐burst’ shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly‐PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly‐PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly‐GA antibody generally detected more DPR than poly‐GP, which in turn was greater than poly‐GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP‐43 positive inclusions in remaining anterior horn cells. Conclusion Degeneration and loss of anterior horn cells associated with expansions in C9orf72 occurs in the absence of DPR, and implies that changes involving loss of nuclear staining for and a cytoplasmic aggregation of TDP‐43 are more likely to be the cause of this. Abundant dipeptide repeat aggregates in regions without neurodegeneration and the sparsity of inclusions in lower motor neurons in cases with motor neuron disease support the conclusion that dipeptide repeat pathology is not the direct cause of neurodegeneration.