Expression of p16 and p21 in the frontal association cortex of ALS/MND brains suggests neuronal cell cycle dysregulation and astrocyte senescence in early stages of the disease.
Neuropathol Appl Neurobiol
; 46(2): 171-185, 2020 02.
Article
in En
| MEDLINE
| ID: mdl-31077599
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 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Cycle
/
Astrocytes
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Cellular Senescence
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p21
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Frontal Lobe
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Amyotrophic Lateral Sclerosis
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Neurons
Type of study:
Risk_factors_studies
Limits:
Aged
/
Aged80
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Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Neuropathol Appl Neurobiol
Year:
2020
Type:
Article
Affiliation country:
United kingdom