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Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Xie C, Ginet V, Sun Y, Koike M, Zhou K, Li T, Li H, Li Q, Wang X, Uchiyama Y, Truttmann AC, Kroemer G, Puyal J, Blomgren K, Zhu C - Autophagy (2016)

Bottom Line: There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI).Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death.Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells.

View Article: PubMed Central - PubMed

Affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

ABSTRACT
Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

No MeSH data available.


Related in: MedlinePlus

Neuronal autophagy is enhanced in the lentiform nucleus of asphyxiated human term newborns. (A) Representative confocal images of LC3B staining (red) in neurons in the lentiform nuclei of human newborns, and quantifications of the numbers of LC3B-positive dots per neuron per μm2 (left histogram) in 6 controls (Ctrl) and 7 hypoxic-ischemic encephalopathy (HIE) cases, showing an increase in autophagosome in all HIE cases. Right histogram showed the average numbers of LC3B-positive dots of control (0.021 ± 0.007) and HIE (0.149 ± 0.018) cases. Representative confocal images of (B) LAMP1 staining (green) and (C) CTSD staining (red) in lentiform nuclei of human newborns and the quantifications of the numbers of positive dots per neuron per μm2 (left histograms) in the different cases individually demonstrated an increase in lysosomes in all HIE cases. Right histograms showed the average numbers of positive dots of control (LAMP1: 0.046 ± 0.005; CTSD: 0.035 ± 0.004) and HIE (LAMP1: 0.172 ± 0.013; CTSD: 0.260 ± 0.014). Quantifications showing the average percentages of (D) LAMP1- and (E) CTSD-positive dots larger than 0.5 μm2 per neuron in control (LAMP1: 2.5 ± 1.9%; CTSD: 2.6 ± 1.8%) and HIE cases (LAMP1: 24.8 ± 6.2%; CTSD: 19.8 ± 3.6%). (F) Representative confocal images of SQSTM1 staining (green) and CTSD (red) in neurons in human newborn lentiform nuclei showed that SQSTM1 expression was not increased (or accumulated) in neurons of HIE cases (right panels) (***, P<0.001).
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f0009: Neuronal autophagy is enhanced in the lentiform nucleus of asphyxiated human term newborns. (A) Representative confocal images of LC3B staining (red) in neurons in the lentiform nuclei of human newborns, and quantifications of the numbers of LC3B-positive dots per neuron per μm2 (left histogram) in 6 controls (Ctrl) and 7 hypoxic-ischemic encephalopathy (HIE) cases, showing an increase in autophagosome in all HIE cases. Right histogram showed the average numbers of LC3B-positive dots of control (0.021 ± 0.007) and HIE (0.149 ± 0.018) cases. Representative confocal images of (B) LAMP1 staining (green) and (C) CTSD staining (red) in lentiform nuclei of human newborns and the quantifications of the numbers of positive dots per neuron per μm2 (left histograms) in the different cases individually demonstrated an increase in lysosomes in all HIE cases. Right histograms showed the average numbers of positive dots of control (LAMP1: 0.046 ± 0.005; CTSD: 0.035 ± 0.004) and HIE (LAMP1: 0.172 ± 0.013; CTSD: 0.260 ± 0.014). Quantifications showing the average percentages of (D) LAMP1- and (E) CTSD-positive dots larger than 0.5 μm2 per neuron in control (LAMP1: 2.5 ± 1.9%; CTSD: 2.6 ± 1.8%) and HIE cases (LAMP1: 24.8 ± 6.2%; CTSD: 19.8 ± 3.6%). (F) Representative confocal images of SQSTM1 staining (green) and CTSD (red) in neurons in human newborn lentiform nuclei showed that SQSTM1 expression was not increased (or accumulated) in neurons of HIE cases (right panels) (***, P<0.001).

Mentions: The presence of autophagosomes was investigated by using LC3B immunohistochemistry and by quantification of the number of LC3B-positive dots in the cytoplasm of individual neurons in the lentiform nuclei. Each of the HIE cases displayed more neuronal LC3B-positive dots (autophagosomes) than the control cases (Fig. 9A). On average, the number of LC3B-positive dots was increased by 7-fold compared to controls, indicating that HIE was accompanied by a considerable induction of autophagosome formation in the lentiform nuclei.Figure 9.


Neuroprotection by selective neuronal deletion of Atg7 in neonatal brain injury.

Xie C, Ginet V, Sun Y, Koike M, Zhou K, Li T, Li H, Li Q, Wang X, Uchiyama Y, Truttmann AC, Kroemer G, Puyal J, Blomgren K, Zhu C - Autophagy (2016)

Neuronal autophagy is enhanced in the lentiform nucleus of asphyxiated human term newborns. (A) Representative confocal images of LC3B staining (red) in neurons in the lentiform nuclei of human newborns, and quantifications of the numbers of LC3B-positive dots per neuron per μm2 (left histogram) in 6 controls (Ctrl) and 7 hypoxic-ischemic encephalopathy (HIE) cases, showing an increase in autophagosome in all HIE cases. Right histogram showed the average numbers of LC3B-positive dots of control (0.021 ± 0.007) and HIE (0.149 ± 0.018) cases. Representative confocal images of (B) LAMP1 staining (green) and (C) CTSD staining (red) in lentiform nuclei of human newborns and the quantifications of the numbers of positive dots per neuron per μm2 (left histograms) in the different cases individually demonstrated an increase in lysosomes in all HIE cases. Right histograms showed the average numbers of positive dots of control (LAMP1: 0.046 ± 0.005; CTSD: 0.035 ± 0.004) and HIE (LAMP1: 0.172 ± 0.013; CTSD: 0.260 ± 0.014). Quantifications showing the average percentages of (D) LAMP1- and (E) CTSD-positive dots larger than 0.5 μm2 per neuron in control (LAMP1: 2.5 ± 1.9%; CTSD: 2.6 ± 1.8%) and HIE cases (LAMP1: 24.8 ± 6.2%; CTSD: 19.8 ± 3.6%). (F) Representative confocal images of SQSTM1 staining (green) and CTSD (red) in neurons in human newborn lentiform nuclei showed that SQSTM1 expression was not increased (or accumulated) in neurons of HIE cases (right panels) (***, P<0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f0009: Neuronal autophagy is enhanced in the lentiform nucleus of asphyxiated human term newborns. (A) Representative confocal images of LC3B staining (red) in neurons in the lentiform nuclei of human newborns, and quantifications of the numbers of LC3B-positive dots per neuron per μm2 (left histogram) in 6 controls (Ctrl) and 7 hypoxic-ischemic encephalopathy (HIE) cases, showing an increase in autophagosome in all HIE cases. Right histogram showed the average numbers of LC3B-positive dots of control (0.021 ± 0.007) and HIE (0.149 ± 0.018) cases. Representative confocal images of (B) LAMP1 staining (green) and (C) CTSD staining (red) in lentiform nuclei of human newborns and the quantifications of the numbers of positive dots per neuron per μm2 (left histograms) in the different cases individually demonstrated an increase in lysosomes in all HIE cases. Right histograms showed the average numbers of positive dots of control (LAMP1: 0.046 ± 0.005; CTSD: 0.035 ± 0.004) and HIE (LAMP1: 0.172 ± 0.013; CTSD: 0.260 ± 0.014). Quantifications showing the average percentages of (D) LAMP1- and (E) CTSD-positive dots larger than 0.5 μm2 per neuron in control (LAMP1: 2.5 ± 1.9%; CTSD: 2.6 ± 1.8%) and HIE cases (LAMP1: 24.8 ± 6.2%; CTSD: 19.8 ± 3.6%). (F) Representative confocal images of SQSTM1 staining (green) and CTSD (red) in neurons in human newborn lentiform nuclei showed that SQSTM1 expression was not increased (or accumulated) in neurons of HIE cases (right panels) (***, P<0.001).
Mentions: The presence of autophagosomes was investigated by using LC3B immunohistochemistry and by quantification of the number of LC3B-positive dots in the cytoplasm of individual neurons in the lentiform nuclei. Each of the HIE cases displayed more neuronal LC3B-positive dots (autophagosomes) than the control cases (Fig. 9A). On average, the number of LC3B-positive dots was increased by 7-fold compared to controls, indicating that HIE was accompanied by a considerable induction of autophagosome formation in the lentiform nuclei.Figure 9.

Bottom Line: There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI).Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death.Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells.

View Article: PubMed Central - PubMed

Affiliation: a Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden.

ABSTRACT
Perinatal asphyxia induces neuronal cell death and brain injury, and is often associated with irreversible neurological deficits in children. There is an urgent need to elucidate the neuronal death mechanisms occurring after neonatal hypoxia-ischemia (HI). We here investigated the selective neuronal deletion of the Atg7 (autophagy related 7) gene on neuronal cell death and brain injury in a mouse model of severe neonatal hypoxia-ischemia. Neuronal deletion of Atg7 prevented HI-induced autophagy, resulted in 42% decrease of tissue loss compared to wild-type mice after the insult, and reduced cell death in multiple brain regions, including apoptosis, as shown by decreased caspase-dependent and -independent cell death. Moreover, we investigated the lentiform nucleus of human newborns who died after severe perinatal asphyxia and found increased neuronal autophagy after severe hypoxic-ischemic encephalopathy compared to control uninjured brains, as indicated by the numbers of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3)-, LAMP1 (lysosomal-associated membrane protein 1)-, and CTSD (cathepsin D)-positive cells. These findings reveal that selective neuronal deletion of Atg7 is strongly protective against neuronal death and overall brain injury occurring after HI and suggest that inhibition of HI-enhanced autophagy should be considered as a potential therapeutic target for the treatment of human newborns developing severe hypoxic-ischemic encephalopathy.

No MeSH data available.


Related in: MedlinePlus