Vazquez-Villaseñor, I., Garwood, C.J., Heath, P.R. et al. (3 more authors) (2020) Expression of p16 and p21 in the frontal association cortex of ALS/MND brains suggest neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease. Neuropathology and Applied Neurobiology, 46 (2). pp. 171-185. ISSN 0305-1846
Abstract
AIMS: Cellular senescence plays a role in organismal ageing and has been linked to persistent DNA damage in age-related diseases. Brain senescence has been described in astrocytes and microglia but is less well understood in neurones. Evidence suggests that neurones activate a senescence-like mechanism that could contribute to neurodegeneration. We aimed to determine whether a persistent DNA damage response (DDR) and senescence activation are features of Motor Neurone Disease (amyotrophic lateral sclerosis, ALS/MND). METHODS: We examined expression of senescence (p16 and p21) and DNA damage markers (8-OHdG and γH2AX) in motor cortex (MCx), frontal association cortex (FACx) and occipital cortex (OCx) in post-mortem tissue donated by patients with ALS/MND and controls. RESULTS: Nuclear expression of p16 and p21 was detected in glial cells; double immunofluorescence for p16/p21 and GFAP suggested that some of these cells were GFAP+ astrocytes. p21 nuclear expression was also found in neurones. Higher levels of p16+ (glia, p= 0.028) and p21+ (glia, p=0.003; neurones, p=0.008) cells were found in the FACx of ALS/MND donors but not in the MCx or OCx. Expression of p16 and p21 did not correlate with 8-OHdG or γH2AX. CONCLUSIONS: Expression of p16 and p21 in glia, mainly in astrocytes, suggests senescence induction in these cells; however, neuronal p21 expression might reflect a more general mechanism of age-related cell cycle dysregulation. The significantly higher proportion of cells expressing either p16 or p21 in the FACx of ALS/MND donors could indicate senescence activation and cell cycle dysregulation in early stages of the disease.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 British Neuropathological Society. This is an author-produced version of a paper subsequently published in Neuropathology and Applied Neurobiology. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | DNA damage; DNA damage response; amyotrophic lateral sclerosis; cell cycle dysregulation; motor neurone disease; oxidative stress; senescence |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/J004308/1 BRITISH NEUROPATHOLOGICAL SOCIETY UNSPECIFIED BRITISH NEUROPATHOLOGICAL SOCIETY NONE |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 29 May 2019 13:45 |
Last Modified: | 03 Dec 2021 11:25 |
Status: | Published |
Publisher: | Wiley |
Refereed: | Yes |
Identification Number: | 10.1111/nan.12559 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:146632 |