title: 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.
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.
authors.affiliation: Department of Clinical Neuropathology, Kings College Hospital, Denmark Hill, London SE5 9RS, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.forename: Andrew
authors.initials: A
authors.lastname: King
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.forename: Satomi
authors.initials: S
authors.lastname: Maekawa
authors.forename: Istvan
authors.initials: I
authors.lastname: Bodi
authors.forename: Boris
authors.initials: B
authors.lastname: Rogelj
authors.forename: Ammar
authors.initials: A
authors.lastname: Al-Chalabi
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Shaw
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology*; D000073885:C9orf72 Protein; D016022:Case-Control Studies; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D004247:DNA / Q000235:genetics; D042622:DNA Repeat Expansion / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000473:pathology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D017966:Pyramidal Cells / Q000378:metabolism / Q000473:pathology; D000071456:Sequestosome-1 Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D004268:DNA-Binding Proteins; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D004247:DNA