p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS

Acta Neuropathol. 2011 Dec;122(6):691-702. doi: 10.1007/s00401-011-0911-2. Epub 2011 Nov 19.

Abstract

Neuronal cytoplasmic inclusions (NCIs) containing phosphorylated TDP-43 (p-TDP-43) are the pathological hallmarks of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and FTLD-TDP. The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. Here we sought to determine whether these cases carry the hexanucleotide repeat expansion in C9orf72. Repeat primer PCR was performed in 36 MND/ALS, FTLD-MND/ALS and FTLD-TDP cases and four controls. Fourteen individuals with the repeat expansion were detected. In all the 14 expansion mutation cases there were abundant globular and star-shaped p62 positive NCIs in the pyramidal cell layer of the hippocampus, the vast majority of which were p-TDP-43 negative. p62 positive NCIs were also abundant in the cerebellar granular and molecular layers in all cases and in Purkinje cells in 12/14 cases but they were only positive for p-TDP-43 in the granular layer of one case. Abundant p62 positive, p-TDP-43 negative neuronal intranuclear inclusions (NIIs) were seen in 12/14 cases in the pyramidal cell layer of the hippocampus and in 6/14 cases in the cerebellar granular layer. This unusual combination of inclusions appears pathognomonic for C9orf72 repeat expansion positive MND/ALS and FTLD-TDP which we believe form a pathologically distinct subset of TDP-43 proteinopathies. Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • C9orf72 Protein
  • Case-Control Studies
  • Cerebellum / metabolism
  • Cerebellum / pathology*
  • DNA / genetics
  • DNA Repeat Expansion / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Female
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / pathology*
  • Hippocampus / metabolism
  • Hippocampus / pathology*
  • Humans
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Intranuclear Inclusion Bodies / metabolism
  • Intranuclear Inclusion Bodies / pathology
  • Male
  • Middle Aged
  • Mutation / genetics
  • Neurons / metabolism*
  • Neurons / pathology
  • Proteins / genetics*
  • Purkinje Cells / metabolism
  • Purkinje Cells / pathology
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • Sequestosome-1 Protein

Substances

  • Adaptor Proteins, Signal Transducing
  • C9orf72 Protein
  • C9orf72 protein, human
  • DNA-Binding Proteins
  • Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • DNA