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

Acta Neuropathol Commun. 2019 Mar 13;7(1):39. doi: 10.1186/s40478-019-0694-6.


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.

Keywords: ALS; C9ORF72; DPRs; ERAD; FTD; HR23B; NGly1; Poly-GA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • C9orf72 Protein / analysis
  • C9orf72 Protein / metabolism*
  • DNA Repair Enzymes / analysis
  • DNA Repair Enzymes / metabolism*
  • DNA-Binding Proteins / analysis
  • DNA-Binding Proteins / metabolism*
  • Female
  • Frontotemporal Dementia / metabolism*
  • Frontotemporal Dementia / pathology
  • Humans
  • Male
  • Middle Aged
  • Protein Aggregates / physiology
  • Proteins / analysis
  • Proteins / metabolism*
  • RNA-Binding Proteins / analysis
  • RNA-Binding Proteins / metabolism*


  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • P62 protein, human
  • Protein Aggregates
  • Proteins
  • RAD23B protein, human
  • RNA-Binding Proteins
  • TARDBP protein, human
  • poly(glycyl-alanyl)
  • DNA Repair Enzymes