Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration

Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon de...
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Autor*in:	Andrea Loreto [verfasserIn] Ciaran S. Hill [verfasserIn] Victoria L. Hewitt [verfasserIn] Giuseppe Orsomando [verfasserIn] Carlo Angeletti [verfasserIn] Jonathan Gilley [verfasserIn] Cristiano Lucci [verfasserIn] Alvaro Sanchez-Martinez [verfasserIn] Alexander J. Whitworth [verfasserIn] Laura Conforti [verfasserIn] Federico Dajas-Bailador [verfasserIn] Michael P. Coleman [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease

Übergeordnetes Werk:	In: Neurobiology of Disease - Elsevier, 2021, 134(2020), Seite -
Übergeordnetes Werk:	volume:134 ; year:2020 ; pages:-

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1016/j.nbd.2019.104678

Katalog-ID:	DOAJ062916483

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520			\|a Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.
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650		4	\|a Mitochondrial dysfunction
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allfields	10.1016/j.nbd.2019.104678 doi (DE-627)DOAJ062916483 (DE-599)DOAJb3991ff6c7554f1da5eaf0b9425b3a69 DE-627 ger DE-627 rakwb eng RC321-571 Andrea Loreto verfasserin aut Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders. Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease Neurosciences. Biological psychiatry. Neuropsychiatry Ciaran S. Hill verfasserin aut Victoria L. Hewitt verfasserin aut Giuseppe Orsomando verfasserin aut Carlo Angeletti verfasserin aut Jonathan Gilley verfasserin aut Cristiano Lucci verfasserin aut Alvaro Sanchez-Martinez verfasserin aut Alexander J. Whitworth verfasserin aut Laura Conforti verfasserin aut Federico Dajas-Bailador verfasserin aut Michael P. Coleman verfasserin aut In Neurobiology of Disease Elsevier, 2021 134(2020), Seite - (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:134 year:2020 pages:- https://doi.org/10.1016/j.nbd.2019.104678 kostenfrei https://doaj.org/article/b3991ff6c7554f1da5eaf0b9425b3a69 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996119303535 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 134 2020 -
spelling	10.1016/j.nbd.2019.104678 doi (DE-627)DOAJ062916483 (DE-599)DOAJb3991ff6c7554f1da5eaf0b9425b3a69 DE-627 ger DE-627 rakwb eng RC321-571 Andrea Loreto verfasserin aut Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders. Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease Neurosciences. Biological psychiatry. Neuropsychiatry Ciaran S. Hill verfasserin aut Victoria L. Hewitt verfasserin aut Giuseppe Orsomando verfasserin aut Carlo Angeletti verfasserin aut Jonathan Gilley verfasserin aut Cristiano Lucci verfasserin aut Alvaro Sanchez-Martinez verfasserin aut Alexander J. Whitworth verfasserin aut Laura Conforti verfasserin aut Federico Dajas-Bailador verfasserin aut Michael P. Coleman verfasserin aut In Neurobiology of Disease Elsevier, 2021 134(2020), Seite - (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:134 year:2020 pages:- https://doi.org/10.1016/j.nbd.2019.104678 kostenfrei https://doaj.org/article/b3991ff6c7554f1da5eaf0b9425b3a69 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996119303535 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 134 2020 -
allfields_unstemmed	10.1016/j.nbd.2019.104678 doi (DE-627)DOAJ062916483 (DE-599)DOAJb3991ff6c7554f1da5eaf0b9425b3a69 DE-627 ger DE-627 rakwb eng RC321-571 Andrea Loreto verfasserin aut Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders. Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease Neurosciences. Biological psychiatry. Neuropsychiatry Ciaran S. Hill verfasserin aut Victoria L. Hewitt verfasserin aut Giuseppe Orsomando verfasserin aut Carlo Angeletti verfasserin aut Jonathan Gilley verfasserin aut Cristiano Lucci verfasserin aut Alvaro Sanchez-Martinez verfasserin aut Alexander J. Whitworth verfasserin aut Laura Conforti verfasserin aut Federico Dajas-Bailador verfasserin aut Michael P. Coleman verfasserin aut In Neurobiology of Disease Elsevier, 2021 134(2020), Seite - (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:134 year:2020 pages:- https://doi.org/10.1016/j.nbd.2019.104678 kostenfrei https://doaj.org/article/b3991ff6c7554f1da5eaf0b9425b3a69 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996119303535 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 134 2020 -
allfieldsGer	10.1016/j.nbd.2019.104678 doi (DE-627)DOAJ062916483 (DE-599)DOAJb3991ff6c7554f1da5eaf0b9425b3a69 DE-627 ger DE-627 rakwb eng RC321-571 Andrea Loreto verfasserin aut Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders. Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease Neurosciences. Biological psychiatry. Neuropsychiatry Ciaran S. Hill verfasserin aut Victoria L. Hewitt verfasserin aut Giuseppe Orsomando verfasserin aut Carlo Angeletti verfasserin aut Jonathan Gilley verfasserin aut Cristiano Lucci verfasserin aut Alvaro Sanchez-Martinez verfasserin aut Alexander J. Whitworth verfasserin aut Laura Conforti verfasserin aut Federico Dajas-Bailador verfasserin aut Michael P. Coleman verfasserin aut In Neurobiology of Disease Elsevier, 2021 134(2020), Seite - (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:134 year:2020 pages:- https://doi.org/10.1016/j.nbd.2019.104678 kostenfrei https://doaj.org/article/b3991ff6c7554f1da5eaf0b9425b3a69 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996119303535 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 134 2020 -
allfieldsSound	10.1016/j.nbd.2019.104678 doi (DE-627)DOAJ062916483 (DE-599)DOAJb3991ff6c7554f1da5eaf0b9425b3a69 DE-627 ger DE-627 rakwb eng RC321-571 Andrea Loreto verfasserin aut Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders. Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease Neurosciences. Biological psychiatry. Neuropsychiatry Ciaran S. Hill verfasserin aut Victoria L. Hewitt verfasserin aut Giuseppe Orsomando verfasserin aut Carlo Angeletti verfasserin aut Jonathan Gilley verfasserin aut Cristiano Lucci verfasserin aut Alvaro Sanchez-Martinez verfasserin aut Alexander J. Whitworth verfasserin aut Laura Conforti verfasserin aut Federico Dajas-Bailador verfasserin aut Michael P. Coleman verfasserin aut In Neurobiology of Disease Elsevier, 2021 134(2020), Seite - (DE-627)268125414 (DE-600)1471408-5 1095953X nnns volume:134 year:2020 pages:- https://doi.org/10.1016/j.nbd.2019.104678 kostenfrei https://doaj.org/article/b3991ff6c7554f1da5eaf0b9425b3a69 kostenfrei http://www.sciencedirect.com/science/article/pii/S0969996119303535 kostenfrei https://doaj.org/toc/1095-953X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2008 GBV_ILN_2014 GBV_ILN_2025 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2064 GBV_ILN_2106 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 134 2020 -
language	English
source	In Neurobiology of Disease 134(2020), Seite - volume:134 year:2020 pages:-
sourceStr	In Neurobiology of Disease 134(2020), Seite - volume:134 year:2020 pages:-
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease Neurosciences. Biological psychiatry. Neuropsychiatry
isfreeaccess_bool	true
container_title	Neurobiology of Disease
authorswithroles_txt_mv	Andrea Loreto @@aut@@ Ciaran S. Hill @@aut@@ Victoria L. Hewitt @@aut@@ Giuseppe Orsomando @@aut@@ Carlo Angeletti @@aut@@ Jonathan Gilley @@aut@@ Cristiano Lucci @@aut@@ Alvaro Sanchez-Martinez @@aut@@ Alexander J. Whitworth @@aut@@ Laura Conforti @@aut@@ Federico Dajas-Bailador @@aut@@ Michael P. Coleman @@aut@@
publishDateDaySort_date	2020-01-01T00:00:00Z
hierarchy_top_id	268125414
id	DOAJ062916483
language_de	englisch
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callnumber-first	R - Medicine
author	Andrea Loreto
spellingShingle	Andrea Loreto misc RC321-571 misc Axon degeneration misc Mitochondrial dysfunction misc NMNAT2 misc SARM1 misc Wallerian degeneration misc Parkinson's disease misc Neurosciences. Biological psychiatry. Neuropsychiatry Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
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topic_title	RC321-571 Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration Axon degeneration Mitochondrial dysfunction NMNAT2 SARM1 Wallerian degeneration Parkinson's disease
topic	misc RC321-571 misc Axon degeneration misc Mitochondrial dysfunction misc NMNAT2 misc SARM1 misc Wallerian degeneration misc Parkinson's disease misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_unstemmed	misc RC321-571 misc Axon degeneration misc Mitochondrial dysfunction misc NMNAT2 misc SARM1 misc Wallerian degeneration misc Parkinson's disease misc Neurosciences. Biological psychiatry. Neuropsychiatry
topic_browse	misc RC321-571 misc Axon degeneration misc Mitochondrial dysfunction misc NMNAT2 misc SARM1 misc Wallerian degeneration misc Parkinson's disease misc Neurosciences. Biological psychiatry. Neuropsychiatry
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title	Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
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title_full	Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
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author_browse	Andrea Loreto Ciaran S. Hill Victoria L. Hewitt Giuseppe Orsomando Carlo Angeletti Jonathan Gilley Cristiano Lucci Alvaro Sanchez-Martinez Alexander J. Whitworth Laura Conforti Federico Dajas-Bailador Michael P. Coleman
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title_sort	mitochondrial impairment activates the wallerian pathway through depletion of nmnat2 leading to sarm1-dependent axon degeneration
callnumber	RC321-571
title_auth	Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
abstract	Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.
abstractGer	Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.
abstract_unstemmed	Wallerian degeneration of physically injured axons involves a well-defined molecular pathway linking loss of axonal survival factor NMNAT2 to activation of pro-degenerative protein SARM1. Manipulating the pathway through these proteins led to the identification of non-axotomy insults causing axon degeneration by a Wallerian-like mechanism, including several involving mitochondrial impairment. Mitochondrial dysfunction is heavily implicated in Parkinson's disease, Charcot-Marie-Tooth disease, hereditary spastic paraplegia and other axonal disorders. However, whether and how mitochondrial impairment activates Wallerian degeneration has remained unclear. Here, we show that disruption of mitochondrial membrane potential leads to axonal NMNAT2 depletion in mouse sympathetic neurons, increasing the substrate-to-product ratio (NMN/NAD) of this NAD-synthesising enzyme, a metabolic fingerprint of Wallerian degeneration. The mechanism appears to involve both impaired NMNAT2 synthesis and reduced axonal transport. Expression of WLDS and Sarm1 deletion both protect axons after mitochondrial uncoupling. Blocking the pathway also confers neuroprotection and increases the lifespan of flies with Pink1 loss-of-function mutation, which causes severe mitochondrial defects. These data indicate that mitochondrial impairment replicates all the major steps of Wallerian degeneration, placing it upstream of NMNAT2 loss, with the potential to contribute to axon pathology in mitochondrial disorders.
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title_short	Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration
url	https://doi.org/10.1016/j.nbd.2019.104678 https://doaj.org/article/b3991ff6c7554f1da5eaf0b9425b3a69 http://www.sciencedirect.com/science/article/pii/S0969996119303535 https://doaj.org/toc/1095-953X
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Mitochondrial impairment activates the Wallerian pathway through depletion of NMNAT2 leading to SARM1-dependent axon degeneration

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