MANF ablation causes prolonged activation of the U
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Posted On: 02/09/2020 2:57:13 AM
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MANF ablation causes prolonged activation of the UPR without neurodegeneration in the mouse midbrain dopamine system
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a lack of MANF from the brain led to the chronic activation of UPR by upregulation of the endoribonuclease activity of the IRE1α pathway. Furthermore, in the aged MANF-deficient mouse brain in addition the PERK and ATF6 branches of the UPR pathways were activated. Neuronal loss in neurodegenerative diseases has been associated with chronic ER stress. In our mouse model, increased UPR activation did not lead to neuronal cell loss in the substantia nigra, decrease of striatal dopamine or behavioural changes of MANF-deficient mice. However, cortical neurons lacking MANF were more vulnerable to chemical induction of additional ER stress in vitro. We conclude that embryonic neuronal deletion of MANF does not cause the loss of midbrain dopamine neurons in mice. However, endogenous MANF is needed for maintenance of neuronal ER homeostasis both in vivo and in vitro.
Significance Statement Exogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) is neuroprotective in animal models of Parkinson’s disease and stroke, but the function of endogenous MANF in neurons is still elusive. This is the first study on the role of endogenous MANF in the adult mouse brain with focus on the midbrain dopamine system. We discovered chronic unfolded protein response (UPR) in the brains of mice lacking MANF. Despite activation of all three UPR pathways, we did not observe degeneration of dopamine neurons, which contrasts to the previously reported detrimental effect of chronic UPR in pancreatic beta cells lacking MANF. Our findings highlight the complexity of the UPR and reveal that the terminal consequences of chronic UPR differ in cell types and context.
https://www.eneuro.org/content/early/2020/01/...77-19.2019
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) localized protein that regulates ER homeostasis and unfolded protein response (UPR). The biology of endogenous MANF in the mammalian brain is unknown and therefore we studied the brain phenotype of MANF-deficient female and male mice at different ages focusing on the midbrain dopamine system and cortical neurons. We show that a lack of MANF from the brain led to the chronic activation of UPR by upregulation of the endoribonuclease activity of the IRE1α pathway. Furthermore, in the aged MANF-deficient mouse brain in addition the PERK and ATF6 branches of the UPR pathways were activated. Neuronal loss in neurodegenerative diseases has been associated with chronic ER stress. In our mouse model, increased UPR activation did not lead to neuronal cell loss in the substantia nigra, decrease of striatal dopamine or behavioural changes of MANF-deficient mice. However, cortical neurons lacking MANF were more vulnerable to chemical induction of additional ER stress in vitro. We conclude that embryonic neuronal deletion of MANF does not cause the loss of midbrain dopamine neurons in mice. However, endogenous MANF is needed for maintenance of neuronal ER homeostasis both in vivo and in vitro.
Significance Statement Exogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) is neuroprotective in animal models of Parkinson’s disease and stroke, but the function of endogenous MANF in neurons is still elusive. This is the first study on the role of endogenous MANF in the adult mouse brain with focus on the midbrain dopamine system. We discovered chronic unfolded protein response (UPR) in the brains of mice lacking MANF. Despite activation of all three UPR pathways, we did not observe degeneration of dopamine neurons, which contrasts to the previously reported detrimental effect of chronic UPR in pancreatic beta cells lacking MANF. Our findings highlight the complexity of the UPR and reveal that the terminal consequences of chronic UPR differ in cell types and context.
https://www.eneuro.org/content/early/2020/01/...77-19.2019
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