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Brain senescence has been described in astrocytes and microglia, but it is less well understood in neurones. Evidence suggests that neurones activate a senescence\u2010like mechanism that could contribute to neurodegeneration. We aimed to determine whether a persistent <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> damage response (<jats:styled-content style=\"fixed-case\">DDR<\/jats:styled-content>) and senescence activation are features of motor neurone disease (amyotrophic lateral sclerosis, <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MND<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We examined expression of senescence (p16 and p21) and <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> damage markers (8\u2010<jats:styled-content style=\"fixed-case\">OH<\/jats:styled-content>dG and \u03b3H2<jats:styled-content style=\"fixed-case\">AX<\/jats:styled-content>) in motor cortex (<jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>x), frontal association cortex (<jats:styled-content style=\"fixed-case\">FAC<\/jats:styled-content>x) and occipital cortex (<jats:styled-content style=\"fixed-case\">OC<\/jats:styled-content>x) in post\u2010mortem tissue donated by patients with <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MND<\/jats:styled-content> and controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Nuclear expression of p16 and p21 was detected in glial cells; double immunofluorescence for p16\/p21 and glial fibrillary acidic protein (<jats:styled-content style=\"fixed-case\">GFAP<\/jats:styled-content>) suggested that some of these cells were <jats:styled-content style=\"fixed-case\">GFAP<\/jats:styled-content><jats:sup>+<\/jats:sup> astrocytes. p21 nuclear expression was also found in neurones. Higher levels of p16<jats:sup>+<\/jats:sup> (glia, <jats:italic>P\u00a0=\u00a00.028<\/jats:italic>) and p21<jats:sup>+<\/jats:sup> (glia, <jats:italic>P\u00a0=\u00a00.003<\/jats:italic>; neurones, <jats:italic>P\u00a0=\u00a00.008<\/jats:italic>) cells were found in the <jats:styled-content style=\"fixed-case\">FAC<\/jats:styled-content>x of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MND<\/jats:styled-content> donors but not in the <jats:styled-content style=\"fixed-case\">MC<\/jats:styled-content>x or <jats:styled-content style=\"fixed-case\">OC<\/jats:styled-content>x. Expression of p16 and p21 did not correlate with 8\u2010<jats:styled-content style=\"fixed-case\">OH<\/jats:styled-content>dG or \u03b3H2<jats:styled-content style=\"fixed-case\">AX<\/jats:styled-content>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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\u2010related cell cycle dysregulation. The significantly higher proportion of cells expressing either p16 or p21 in the <jats:styled-content style=\"fixed-case\">FAC<\/jats:styled-content>x of <jats:styled-content style=\"fixed-case\">ALS<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">MND<\/jats:styled-content> donors could indicate senescence activation and cell cycle dysregulation in early stages of the disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/nan.12559","type":"journal-article","created":{"date-parts":[[2019,5,11]],"date-time":"2019-05-11T19:23:09Z","timestamp":1557602589000},"page":"171-185","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":84,"title":["Expression of p16 and p21 in the frontal association cortex of <scp>ALS<\/scp>\/<scp>MND<\/scp> brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1668-7797","authenticated-orcid":false,"given":"I.","family":"Vazquez\u2010Villase\u00f1or","sequence":"first","affiliation":[{"name":"Sheffield Institute for Translational Neuroscience University of Sheffield Sheffield UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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