Abstract
Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases, including frontotemporal dementia (FTD), Huntington’s disease (HD), spinocerebellar ataxia type 3 and 7 (SCA3/7), fragile X associated tremor/ataxia syndrome (FXTAS) and Parkinson’s disease (PD). Here, we describe HR23B pathology in C9ORF72 linked FTD and amyotrophic lateral sclerosis (ALS) cases. HR23B presented in neuropils, intranuclear inclusions and cytoplasmic and perinuclear inclusions and was predominantly found in cortices (frontal, temporal and motor), spinal cord and hippocampal dentate gyrus. HR23B co-localized with poly-GA-, pTDP-43- and p62-positive inclusions in frontal cortex and in hippocampal dentate gyrus, the latter showing higher co-localization percentages. HR23B binding partners XPC, 20S and ataxin-3, which are involved in nucleotide excision repair (NER) and the ubiquitin-proteasome system (UPS), did not show an aberrant distribution. However, C9ORF72 fibroblasts were more sensitive for UV-C damage than healthy control fibroblasts, even though all factors involved in NER localized normally to DNA damage and the efficiency of DNA repair was not reduced. HR23Bs other binding partner NGly1/PNGase, involved in ER-associated degradation (ERAD) of misfolded proteins, was not expressed in the majority of neurons in C9FTD/ALS brain sections compared to non-demented controls. Our results suggest a difference in HR23B aggregation and co-localization pattern with DPRs, pTDP-43 and p62 between different brain areas from C9FTD/ALS cases. We hypothesize that HR23B may play a role in C9ORF72 pathogenesis, possibly by aberrant ERAD functioning.
Highlights
The hexanucleotide (G4C2) repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) [12, 33]
Characterizing Ran-GAP, ADARB2, HR23B, fragile X mental retardation protein (FMRP) and Puralpha in a cohort of C9FTD patients and non-demented controls We started with assessing the localization of ras-related nuclear protein GTPase activating protein (Ran-GAP) in C9FTD patient brain sections
We found 60.6% of HR23B inclusions being positive for poly-GA in the dentate gyrus, which is nearly a 10-fold increase compared to the frontal cortex (Fig. 4 and Additional file 9: Table S2)
Summary
The hexanucleotide (G4C2) repeat expansion in the chromosome 9 open reading frame 72 (C9ORF72) gene is the most common genetic cause of FTD and ALS [12, 33]. CpG promoter region of the C9ORF72 gene leading to haploinsufficiency [5, 43], 2) retention of repeat containing intron 1 in mRNAs causing RNA foci to appear in both nucleus and cytoplasm that sequester RNA-binding proteins [11, 27] or 3) the production of dipeptide repeats (DPR) by unconventional repeat-associated non-AUG (RAN) translation of the repeat [2, 18, 31] These DPRs are produced from both sense and antisense transcripts resulting in 5 possibly toxic peptides (poly-GA, −GP, −GR, −PR and -PA) and are found as inclusions in post-mortem brain material of C9ORF72 carriers [28, 38]. Constituents of inclusions in human C9FTD/ALS brain material might provide a tool to identify key players in neurodegeneration
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