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

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 it 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 glial fibrillary acidic protein (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.