HR23B pathology preferentially co-localizes with p62, pTDP-43 and poly-GA in C9ORF72-linked frontotemporal dementia and amyotrophic lateral sclerosis

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.Electronic supplementary materialThe online version of this article (10.1186/s40478-019-0694-6) contains supplementary material, which is available to authorized users.

Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency

“…Several of the proteins accumulated in polyglucosan are present in protein aggregate myopathies like myotilinopathy and filaminopathy, for example, HSPB1, alpha‐crystallin B chain, p62, VCP and the muscle‐specific intermediate filament desmin 37,42 . Protein components found in polyglucosan of patients with RBCK1 deficiency are also seen in protein aggregates of frontotemporal dementia and amyotrophic lateral sclerosis, for example, UCHL‐1 and RAD23B 43,44 . These similarities between polyglucosan and well‐established protein aggregate diseases indicate that protein aggregation is a contributing factor for the establishment and persistence of polyglucosan bodies.…”

Human ALS/FTD brain organoid slice cultures display distinct early astrocyte and targetable neuronal pathology

“…4b–d ), a result previously reported for C9 ALS/FTD brain samples 34 . This was accompanied by a 2.67-fold increase in PABP1 levels, a stress granule marker 35 , and a 1.86-fold increase in the total P62 protein content, an autophagy signaling protein and also a broad indicator of ER stress in C9 ALS/FTD 36 (Fig. 4b–d ).…”

Multiple pathways of toxicity induced by C9orf72 dipeptide repeat aggregates and G4C2 RNA in a cellular model

“…Moreover, R-DPRs can interact with membrane-free phase-separated compartments, such as the nucleolus, causing nucleolar stress and dysfunction of nucleolar quality control, impairment of nucleocytoplasmic trafficking and protein translation, as well as induction of stress granule formation ( Frottin et al, 2019 ; Hayes et al, 2020 ; Kanekura et al, 2016 ; Kwon et al, 2014 ; Lee et al, 2016 ; Mizielinska et al, 2017 ; Moens et al, 2019 ; Radwan et al, 2020 ; Shi et al, 2017 ; Tao et al, 2015 ; Vanneste et al, 2019 ; White et al, 2019 ; Yamakawa et al, 2015 ; Zhang et al, 2018b ). Additionally, cytoplasmic poly-GA aggregates associate extensively with proteasomes and other components of the ubiquitin proteasome system, and interfere with proteasome activity ( Al-Sarraj et al, 2011 ; Guo et al, 2018 ; Khosravi et al, 2020 ; May et al, 2014 ; Mori et al, 2013c ; Riemslagh et al, 2019 ), as well as induce mislocalization of nuclear proteins ( Khosravi et al, 2017 ; Nihei et al, 2020 ; Nonaka et al, 2018 ; Solomon et al, 2018 ). In mice expressing poly-GA, the aggregates have also been observed to sequester nuclear pore components ( Zhang et al, 2016 ), thereby interfering with nucleocytoplasmic protein transport.…”