Circadian sleep/wake-associated cells show dipeptide repeat protein aggregates in C9orf72-related ALS and FTLD cases

Lieselot Dedeene,Rik Vandenberghe,Koen Poesen,Evelien Van Schoor,Dietmar Rudolf Thal,Philip Van Damme

doi:10.1186/s40478-019-0845-9

Abstract

Motor-, behavior- and/or cognition-related symptoms are key hallmarks in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLD-TDP), respectively. It has been reported that these patients also experience sleep disturbances, which might implicate a disturbed circadian rhythm of the sleep/wake cycle. It remains unknown, however, whether cells involved in the circadian sleep/wake cycle are affected by ALS- and FTLD-related neuropathological changes including phosphorylated TDP-43 (pTDP-43) aggregates and dipeptide repeat protein (DPR) inclusions resulting from the C9orf72 hexanucleotide repeat expansion. Immunohistochemistry for DPR and pTDP-43 pathology was performed in post-mortem hypothalamus and pineal gland tissue of patients with ALS and/or FTLD-TDP with and without the C9orf72 repeat expansion and healthy controls. Circadian sleep/wake-associated cells, including pinealocytes and hypothalamic neurons related to the suprachiasmatic nucleus (SCN), were microscopically assessed. We observed numerous DPR inclusions (poly(GA), poly(GP), poly(GR) and poly(PR)) in the pinealocytes and few poly(GA) inclusions in the SCN-related neurons in C9orf72-related ALS and/or FTLD-TDP cases. These circadian sleep/wake-associated cells, however, were devoid of pTDP-43 pathology both in C9orf72- and nonC9orf72-related ALS and/or FTLD-TDP cases. Our neuropathological findings show that pinealocytes and, to a lesser extent, SCN-related neurons are affected by DPR pathology. This may reflect an involvement of these cells in sleep/wake disturbances observed in ALS and/or FTLD-TDP patients.

Highlights

The hexanucleotide (GGGGCC) repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene is the underlying genetic cause in approximately half of the familial amyotrophic lateral sclerosis (ALS) cases and in about 10% of the sporadic ALS cases [18]
We immunohistochemically investigated circadian sleep/wake-associated cells for the presence of ALS- and frontotemporal lobar degeneration (FTLD)-TDPrelated pathological protein inclusions (DPRs and phosphorylated transactive response DNA-binding protein 43 kDa (TDP-43)) in patients with ALS and/or FTLD-TDP with and without the C9orf72 repeat expansion
Abundant dipeptide repeat protein (DPR) pathology in the pineal gland of C9orf72 cases The neuropathological diagnosis, sex and age by study groups is shown in Table 1 and a list of the individual cases included in this study is provided in Additional file 1

Summary

Introduction

The hexanucleotide (GGGGCC) repeat expansion in the chromosome 9 open reading frame 72 (C9orf72) gene is the underlying genetic cause in approximately half of the familial amyotrophic lateral sclerosis (ALS) cases and in about 10% of the sporadic ALS cases [18]. This C9orf repeat expansion connects ALS to frontotemporal lobar degeneration with. One study showed a potential involvement of the C9orf repeat expansion in rapid eye movement sleep behavior disorder (RBD) by identifying two C9orf repeat expansion carriers in a cohort of 344 RBD patients [13] These two RBD patients were carriers of a risk haplotype associated with C9orf72-related ALS and FTLD [29]. Studies providing an in-depth characterization of the previously mentioned sleep problems in ALS and/or FTLD-TDP patients with and without the C9orf repeat expansion are yet to be performed

Methods

Results

Discussion

Conclusion