Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB
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Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB. / D'Acunto, E; Gianfrancesco, L; Serangeli, I; D'Orsi, M; Sabato, V; Guadagno, N A; Bhosale, G; Caristi, S; Failla, A V; De Jaco, A; Cacci, E; Duchen, M R; Lupo, G; Galliciotti, G; Miranda, E.
In: CELL MOL LIFE SCI, Vol. 79, No. 8, 21.07.2022, p. 437.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Polymerogenic neuroserpin causes mitochondrial alterations and activates NFκB but not the UPR in a neuronal model of neurodegeneration FENIB
AU - D'Acunto, E
AU - Gianfrancesco, L
AU - Serangeli, I
AU - D'Orsi, M
AU - Sabato, V
AU - Guadagno, N A
AU - Bhosale, G
AU - Caristi, S
AU - Failla, A V
AU - De Jaco, A
AU - Cacci, E
AU - Duchen, M R
AU - Lupo, G
AU - Galliciotti, G
AU - Miranda, E
N1 - © 2022. The Author(s).
PY - 2022/7/21
Y1 - 2022/7/21
N2 - The neurodegenerative condition FENIB (familiar encephalopathy with neuroserpin inclusion bodies) is caused by heterozygous expression of polymerogenic mutant neuroserpin (NS), with polymer deposition within the endoplasmic reticulum (ER) of neurons. We generated transgenic neural progenitor cells (NPCs) from mouse fetal cerebral cortex stably expressing either the control protein GFP or human wild type, polymerogenic G392E or truncated (delta) NS. This cellular model makes it possible to study the toxicity of polymerogenic NS in the appropriated cell type by in vitro differentiation to neurons. Our previous work showed that expression of G392E NS in differentiated NPCs induced an adaptive response through the upregulation of several genes involved in the defence against oxidative stress, and that pharmacological reduction of the antioxidant defences by drug treatments rendered G392E NS neurons more susceptible to apoptosis than control neurons. In this study, we assessed mitochondrial distribution and found a higher percentage of perinuclear localisation in G392E NS neurons, particularly in those containing polymers, a phenotype that was enhanced by glutathione chelation and rescued by antioxidant molecules. Mitochondrial membrane potential and contact sites between mitochondria and the ER were reduced in neurons expressing the G392E mutation. These alterations were associated with a pattern of ER stress that involved the ER overload response but not the unfolded protein response. Our results suggest that intracellular accumulation of NS polymers affects the interaction between the ER and mitochondria, causing mitochondrial alterations that contribute to the neuronal degeneration seen in FENIB patients.
AB - The neurodegenerative condition FENIB (familiar encephalopathy with neuroserpin inclusion bodies) is caused by heterozygous expression of polymerogenic mutant neuroserpin (NS), with polymer deposition within the endoplasmic reticulum (ER) of neurons. We generated transgenic neural progenitor cells (NPCs) from mouse fetal cerebral cortex stably expressing either the control protein GFP or human wild type, polymerogenic G392E or truncated (delta) NS. This cellular model makes it possible to study the toxicity of polymerogenic NS in the appropriated cell type by in vitro differentiation to neurons. Our previous work showed that expression of G392E NS in differentiated NPCs induced an adaptive response through the upregulation of several genes involved in the defence against oxidative stress, and that pharmacological reduction of the antioxidant defences by drug treatments rendered G392E NS neurons more susceptible to apoptosis than control neurons. In this study, we assessed mitochondrial distribution and found a higher percentage of perinuclear localisation in G392E NS neurons, particularly in those containing polymers, a phenotype that was enhanced by glutathione chelation and rescued by antioxidant molecules. Mitochondrial membrane potential and contact sites between mitochondria and the ER were reduced in neurons expressing the G392E mutation. These alterations were associated with a pattern of ER stress that involved the ER overload response but not the unfolded protein response. Our results suggest that intracellular accumulation of NS polymers affects the interaction between the ER and mitochondria, causing mitochondrial alterations that contribute to the neuronal degeneration seen in FENIB patients.
KW - Animals
KW - Antioxidants/metabolism
KW - Endoplasmic Reticulum Stress
KW - Epilepsies, Myoclonic
KW - Heredodegenerative Disorders, Nervous System
KW - Humans
KW - Mice
KW - NF-kappa B/metabolism
KW - Neurons/metabolism
KW - Neuropeptides
KW - Polymers
KW - Serpins
U2 - 10.1007/s00018-022-04463-3
DO - 10.1007/s00018-022-04463-3
M3 - SCORING: Journal article
C2 - 35864382
VL - 79
SP - 437
JO - CELL MOL LIFE SCI
JF - CELL MOL LIFE SCI
SN - 1420-682X
IS - 8
ER -