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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

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Al-Sarraj, Safa, King, Andrew, Troakes, Claire, Smith, Bradley, Maekawa, Satomi, Bodi, Istvan, Rogelj, Boris, Al-Chalabi, Ammar, Hortobágyi, Tibor, Shaw, Christopher E.·2011·Acta Neuropathologica

DOI 10.1007/s00401-011-0911-2

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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.

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Authors: Al-Sarraj, S., King, A., Troakes, C., Smith, B., Maekawa, S., Bodi, I., Rogelj, B., Al-Chalabi, A., Hortobágyi, T., & Shaw, C. E.
Affiliations: King's College London (GB)
Corresponding author: King, Andrew
ORCID: King, Andrew
Troakes, Claire
Smith, Bradley
Rogelj, Boris
Hortobágyi, Tibor
Shaw, Christopher E.
Venue: Acta Neuropathologica
Publisher: Springer Science and Business Media LLC
Published: 2011-11-19
Volume: 122
Issue: 6
Pages: 691-702
ISSN: 0001-6322 (ISSN-L)
1432-0533
DOI: 10.1007/s00401-011-0911-2
OpenAlex: W2066002405
Cited by: 475
References: 35
Citations by year: 2026: 9 · 2025: 9 · 2024: 22 · 2023: 24 · 2022: 23 · 2021: 23 · 2020: 40 · 2019: 27 · 2018: 24 · 2017: 39 · 2016: 38 · 2015: 41 · 2014: 42 · 2013: 63 · 2012: 45
FWCI: 31.22
Type: journal article
Language: en
Open access: green
hdl.handle.net
Licence: other-oa
www.springer.com/tdm (tdm)
Locations: Acta Neuropathologica (publishedVersion)
PubMed (publishedVersion)
University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion, other-oa)
Research Portal (King's College London) (submittedVersion)
Funders: Wellcome Trust (089701)
Medical Research Council (MC_G1000733)
Topics: Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords: p62, TDP-43, C9orf72, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, motor neuron disease, frontotemporal lobar degeneration, FTLD-TDP, neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, cerebellum, hippocampus, Purkinje cells, neurodegeneration, protein aggregation
MeSH terms: Sequestosome-1 Protein, C9orf72 Protein, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Inclusion Bodies, Cerebellum, DNA, DNA-Binding Proteins, Female, Hippocampus, Humans, Male, Middle Aged, Mutation, Neurons, Proteins, Purkinje Cells, Case-Control Studies, Pyramidal Cells, DNA Repeat Expansion, Intranuclear Inclusion Bodies, Adaptor Proteins, Signal Transducing, Frontotemporal Lobar Degeneration

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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

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