An MND/ALS phenotype associated with C9orf72 repeat expansion: Abundant p62‐positive, TDP‐43‐negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline
Abstract
The transactive response DNA binding protein (TDP‐43) proteinopathies describe a clinico‐pathological spectrum of multi‐system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP‐43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP‐43‐positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star‐shaped p62‐immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP‐43‐positive inclusions were sparse. This pattern was also seen in the cerebellum where p62‐positive, TDP‐43‐negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD‐TDP, showed high p62 levels and low TDP‐43 levels with no high molecular weight smearing. MND/ALS‐associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9‐linked MND/ALS and FTLD. We conclude that these chromosome 9‐linked MND/ALS cases represent a pathological sub‐group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.
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In C9orf72-related ALS and FTD, SQSTM1 accumulates together with ubiquitin in neurons and glia as well as muscle fibers.
“In the most commonly inherited form of ALS and FTD due to mutations in the C9orf72 gene (described below), SQSTM1 accumulates together with ubiquitin in neurons and glia [119–121] as well as muscle fibers [122].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [121]
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- Authors
- Troakes, C., Maekawa, S., Wijesekera, L., Rogelj, B., Siklós, L., Bell, C., Smith, B., Newhouse, S., Vance, C., Johnson, L., Hortobágyi, T., Shatunov, A., Al‐Chalabi, A., Leigh, N., Shaw, C. E., King, A., & Al‐Sarraj, S.
- Affiliations
- King's College London (GB)
- HUN-REN Szegedi Biológiai Kutatóközpont (HU)
- Corresponding author
- Troakes, Claire
- ORCID
- Venue
- Neuropathology
- Publisher
- Wiley
- Published
- 2011-12-19
- Volume
- 32
- Issue
- 5
- Pages
- 505-514
- ISSN
- 0919-6544 (ISSN-L)
- 1440-1789
- OpenAlex
- W2090365926
- Cited by
- 124
- References
- 40
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 9 · 2020: 5 · 2019: 6 · 2018: 5 · 2017: 9 · 2016: 7 · 2015: 16 · 2014: 9 · 2013: 14 · 2012: 25
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropathology (publishedVersion)
- PubMed (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Wellcome Trust (089701)
- Nemzeti Kutatási és Technológiai Hivatal
- Medical Research Council (MC_G1000733)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- C9orf72 repeat expansion, amyotrophic lateral sclerosis, motor neuron disease, TDP-43 proteinopathy, p62, neuronal cytoplasmic inclusions, cerebellar granule cells, hippocampus, cerebral cortex, FTLD-TDP, lower motor neuron involvement
- MeSH terms
- C9orf72 Protein, Amyotrophic Lateral Sclerosis, Brain, Inclusion Bodies, Cerebellum, Cerebral Cortex, Cognition Disorders, DNA, DNA-Binding Proteins, Female, Fluorescent Antibody Technique, Hippocampus, Humans, Immunohistochemistry, Male, Microscopy, Electron, Middle Aged, Proteins, Spinal Cord, Tissue Banks, Blotting, Western, Proto-Oncogene Proteins c-myc, Motor Neuron Disease, Age of Onset, Trinucleotide Repeat Expansion
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