VCP suppresses proteopathic seeding in neurons

Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Jiang Zhu [verfasserIn] Sara Pittman [verfasserIn] Dhruva Dhavale [verfasserIn] Rachel French [verfasserIn] Jessica N. Patterson [verfasserIn] Mohamed Salman Kaleelurrrahuman [verfasserIn] Yuanzi Sun [verfasserIn] Jaime Vaquer-Alicea [verfasserIn] Gianna Maggiore [verfasserIn] Christoph S. Clemen [verfasserIn] William J. Buscher [verfasserIn] Jan Bieschke [verfasserIn] Paul Kotzbauer [verfasserIn] Yuna Ayala [verfasserIn] Marc I. Diamond [verfasserIn] Albert A. Davis [verfasserIn] Conrad Weihl [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia

Übergeordnetes Werk:	In: Molecular Neurodegeneration - BMC, 2007, 17(2022), 1, Seite 25
Übergeordnetes Werk:	volume:17 ; year:2022 ; number:1 ; pages:25

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13024-022-00532-0

Katalog-ID:	DOAJ032008007

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520			\|a Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.
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650		4	\|a Alpha-synuclein
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650		4	\|a Frontotemporal dementia
653		0	\|a Neurology. Diseases of the nervous system
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700	0		\|a Sara Pittman \|e verfasserin \|4 aut
700	0		\|a Dhruva Dhavale \|e verfasserin \|4 aut
700	0		\|a Rachel French \|e verfasserin \|4 aut
700	0		\|a Jessica N. Patterson \|e verfasserin \|4 aut
700	0		\|a Mohamed Salman Kaleelurrrahuman \|e verfasserin \|4 aut
700	0		\|a Yuanzi Sun \|e verfasserin \|4 aut
700	0		\|a Jaime Vaquer-Alicea \|e verfasserin \|4 aut
700	0		\|a Gianna Maggiore \|e verfasserin \|4 aut
700	0		\|a Christoph S. Clemen \|e verfasserin \|4 aut
700	0		\|a William J. Buscher \|e verfasserin \|4 aut
700	0		\|a Jan Bieschke \|e verfasserin \|4 aut
700	0		\|a Paul Kotzbauer \|e verfasserin \|4 aut
700	0		\|a Yuna Ayala \|e verfasserin \|4 aut
700	0		\|a Marc I. Diamond \|e verfasserin \|4 aut
700	0		\|a Albert A. Davis \|e verfasserin \|4 aut
700	0		\|a Conrad Weihl \|e verfasserin \|4 aut
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allfields	10.1186/s13024-022-00532-0 doi (DE-627)DOAJ032008007 (DE-599)DOAJ47c9b932aac447af8c16f13a657d0a0e DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Jiang Zhu verfasserin aut VCP suppresses proteopathic seeding in neurons 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP. CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia Neurology. Diseases of the nervous system Geriatrics Sara Pittman verfasserin aut Dhruva Dhavale verfasserin aut Rachel French verfasserin aut Jessica N. Patterson verfasserin aut Mohamed Salman Kaleelurrrahuman verfasserin aut Yuanzi Sun verfasserin aut Jaime Vaquer-Alicea verfasserin aut Gianna Maggiore verfasserin aut Christoph S. Clemen verfasserin aut William J. Buscher verfasserin aut Jan Bieschke verfasserin aut Paul Kotzbauer verfasserin aut Yuna Ayala verfasserin aut Marc I. Diamond verfasserin aut Albert A. Davis verfasserin aut Conrad Weihl verfasserin aut In Molecular Neurodegeneration BMC, 2007 17(2022), 1, Seite 25 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:17 year:2022 number:1 pages:25 https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/article/47c9b932aac447af8c16f13a657d0a0e kostenfrei https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 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_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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 17 2022 1 25
spelling	10.1186/s13024-022-00532-0 doi (DE-627)DOAJ032008007 (DE-599)DOAJ47c9b932aac447af8c16f13a657d0a0e DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Jiang Zhu verfasserin aut VCP suppresses proteopathic seeding in neurons 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP. CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia Neurology. Diseases of the nervous system Geriatrics Sara Pittman verfasserin aut Dhruva Dhavale verfasserin aut Rachel French verfasserin aut Jessica N. Patterson verfasserin aut Mohamed Salman Kaleelurrrahuman verfasserin aut Yuanzi Sun verfasserin aut Jaime Vaquer-Alicea verfasserin aut Gianna Maggiore verfasserin aut Christoph S. Clemen verfasserin aut William J. Buscher verfasserin aut Jan Bieschke verfasserin aut Paul Kotzbauer verfasserin aut Yuna Ayala verfasserin aut Marc I. Diamond verfasserin aut Albert A. Davis verfasserin aut Conrad Weihl verfasserin aut In Molecular Neurodegeneration BMC, 2007 17(2022), 1, Seite 25 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:17 year:2022 number:1 pages:25 https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/article/47c9b932aac447af8c16f13a657d0a0e kostenfrei https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 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_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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 17 2022 1 25
allfields_unstemmed	10.1186/s13024-022-00532-0 doi (DE-627)DOAJ032008007 (DE-599)DOAJ47c9b932aac447af8c16f13a657d0a0e DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Jiang Zhu verfasserin aut VCP suppresses proteopathic seeding in neurons 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP. CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia Neurology. Diseases of the nervous system Geriatrics Sara Pittman verfasserin aut Dhruva Dhavale verfasserin aut Rachel French verfasserin aut Jessica N. Patterson verfasserin aut Mohamed Salman Kaleelurrrahuman verfasserin aut Yuanzi Sun verfasserin aut Jaime Vaquer-Alicea verfasserin aut Gianna Maggiore verfasserin aut Christoph S. Clemen verfasserin aut William J. Buscher verfasserin aut Jan Bieschke verfasserin aut Paul Kotzbauer verfasserin aut Yuna Ayala verfasserin aut Marc I. Diamond verfasserin aut Albert A. Davis verfasserin aut Conrad Weihl verfasserin aut In Molecular Neurodegeneration BMC, 2007 17(2022), 1, Seite 25 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:17 year:2022 number:1 pages:25 https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/article/47c9b932aac447af8c16f13a657d0a0e kostenfrei https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 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_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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 17 2022 1 25
allfieldsGer	10.1186/s13024-022-00532-0 doi (DE-627)DOAJ032008007 (DE-599)DOAJ47c9b932aac447af8c16f13a657d0a0e DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Jiang Zhu verfasserin aut VCP suppresses proteopathic seeding in neurons 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP. CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia Neurology. Diseases of the nervous system Geriatrics Sara Pittman verfasserin aut Dhruva Dhavale verfasserin aut Rachel French verfasserin aut Jessica N. Patterson verfasserin aut Mohamed Salman Kaleelurrrahuman verfasserin aut Yuanzi Sun verfasserin aut Jaime Vaquer-Alicea verfasserin aut Gianna Maggiore verfasserin aut Christoph S. Clemen verfasserin aut William J. Buscher verfasserin aut Jan Bieschke verfasserin aut Paul Kotzbauer verfasserin aut Yuna Ayala verfasserin aut Marc I. Diamond verfasserin aut Albert A. Davis verfasserin aut Conrad Weihl verfasserin aut In Molecular Neurodegeneration BMC, 2007 17(2022), 1, Seite 25 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:17 year:2022 number:1 pages:25 https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/article/47c9b932aac447af8c16f13a657d0a0e kostenfrei https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 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_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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 17 2022 1 25
allfieldsSound	10.1186/s13024-022-00532-0 doi (DE-627)DOAJ032008007 (DE-599)DOAJ47c9b932aac447af8c16f13a657d0a0e DE-627 ger DE-627 rakwb eng RC346-429 RC952-954.6 Jiang Zhu verfasserin aut VCP suppresses proteopathic seeding in neurons 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP. CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia Neurology. Diseases of the nervous system Geriatrics Sara Pittman verfasserin aut Dhruva Dhavale verfasserin aut Rachel French verfasserin aut Jessica N. Patterson verfasserin aut Mohamed Salman Kaleelurrrahuman verfasserin aut Yuanzi Sun verfasserin aut Jaime Vaquer-Alicea verfasserin aut Gianna Maggiore verfasserin aut Christoph S. Clemen verfasserin aut William J. Buscher verfasserin aut Jan Bieschke verfasserin aut Paul Kotzbauer verfasserin aut Yuna Ayala verfasserin aut Marc I. Diamond verfasserin aut Albert A. Davis verfasserin aut Conrad Weihl verfasserin aut In Molecular Neurodegeneration BMC, 2007 17(2022), 1, Seite 25 (DE-627)515978361 (DE-600)2244557-2 17501326 nnns volume:17 year:2022 number:1 pages:25 https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/article/47c9b932aac447af8c16f13a657d0a0e kostenfrei https://doi.org/10.1186/s13024-022-00532-0 kostenfrei https://doaj.org/toc/1750-1326 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 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_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 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 17 2022 1 25
language	English
source	In Molecular Neurodegeneration 17(2022), 1, Seite 25 volume:17 year:2022 number:1 pages:25
sourceStr	In Molecular Neurodegeneration 17(2022), 1, Seite 25 volume:17 year:2022 number:1 pages:25
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia Neurology. Diseases of the nervous system Geriatrics
isfreeaccess_bool	true
container_title	Molecular Neurodegeneration
authorswithroles_txt_mv	Jiang Zhu @@aut@@ Sara Pittman @@aut@@ Dhruva Dhavale @@aut@@ Rachel French @@aut@@ Jessica N. Patterson @@aut@@ Mohamed Salman Kaleelurrrahuman @@aut@@ Yuanzi Sun @@aut@@ Jaime Vaquer-Alicea @@aut@@ Gianna Maggiore @@aut@@ Christoph S. Clemen @@aut@@ William J. Buscher @@aut@@ Jan Bieschke @@aut@@ Paul Kotzbauer @@aut@@ Yuna Ayala @@aut@@ Marc I. Diamond @@aut@@ Albert A. Davis @@aut@@ Conrad Weihl @@aut@@
publishDateDaySort_date	2022-01-01T00:00:00Z
hierarchy_top_id	515978361
id	DOAJ032008007
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">DOAJ032008007</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230502204142.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230226s2022 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s13024-022-00532-0</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)DOAJ032008007</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-599)DOAJ47c9b932aac447af8c16f13a657d0a0e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC346-429</subfield></datafield><datafield tag="050" ind1=" " ind2="0"><subfield code="a">RC952-954.6</subfield></datafield><datafield tag="100" ind1="0" ind2=" "><subfield code="a">Jiang Zhu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">VCP suppresses proteopathic seeding in neurons</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CRISPR screen</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Seeding</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Alpha-synuclein</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">TDP-43</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Frontotemporal dementia</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neurology. 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callnumber-first	R - Medicine
author	Jiang Zhu
spellingShingle	Jiang Zhu misc RC346-429 misc RC952-954.6 misc CRISPR screen misc Seeding misc Alpha-synuclein misc TDP-43 misc Frontotemporal dementia misc Neurology. Diseases of the nervous system misc Geriatrics VCP suppresses proteopathic seeding in neurons
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topic_title	RC346-429 RC952-954.6 VCP suppresses proteopathic seeding in neurons CRISPR screen Seeding Alpha-synuclein TDP-43 Frontotemporal dementia
topic	misc RC346-429 misc RC952-954.6 misc CRISPR screen misc Seeding misc Alpha-synuclein misc TDP-43 misc Frontotemporal dementia misc Neurology. Diseases of the nervous system misc Geriatrics
topic_unstemmed	misc RC346-429 misc RC952-954.6 misc CRISPR screen misc Seeding misc Alpha-synuclein misc TDP-43 misc Frontotemporal dementia misc Neurology. Diseases of the nervous system misc Geriatrics
topic_browse	misc RC346-429 misc RC952-954.6 misc CRISPR screen misc Seeding misc Alpha-synuclein misc TDP-43 misc Frontotemporal dementia misc Neurology. Diseases of the nervous system misc Geriatrics
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hierarchy_parent_title	Molecular Neurodegeneration
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title	VCP suppresses proteopathic seeding in neurons
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title_full	VCP suppresses proteopathic seeding in neurons
author_sort	Jiang Zhu
journal	Molecular Neurodegeneration
journalStr	Molecular Neurodegeneration
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author_browse	Jiang Zhu Sara Pittman Dhruva Dhavale Rachel French Jessica N. Patterson Mohamed Salman Kaleelurrrahuman Yuanzi Sun Jaime Vaquer-Alicea Gianna Maggiore Christoph S. Clemen William J. Buscher Jan Bieschke Paul Kotzbauer Yuna Ayala Marc I. Diamond Albert A. Davis Conrad Weihl
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format_se	Elektronische Aufsätze
author-letter	Jiang Zhu
doi_str_mv	10.1186/s13024-022-00532-0
author2-role	verfasserin
title_sort	vcp suppresses proteopathic seeding in neurons
callnumber	RC346-429
title_auth	VCP suppresses proteopathic seeding in neurons
abstract	Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.
abstractGer	Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.
abstract_unstemmed	Abstract Background Neuronal uptake and subsequent spread of proteopathic seeds, such as αS (alpha-synuclein), Tau, and TDP-43, contribute to neurodegeneration. The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.
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title_short	VCP suppresses proteopathic seeding in neurons
url	https://doi.org/10.1186/s13024-022-00532-0 https://doaj.org/article/47c9b932aac447af8c16f13a657d0a0e https://doaj.org/toc/1750-1326
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author2	Sara Pittman Dhruva Dhavale Rachel French Jessica N. Patterson Mohamed Salman Kaleelurrrahuman Yuanzi Sun Jaime Vaquer-Alicea Gianna Maggiore Christoph S. Clemen William J. Buscher Jan Bieschke Paul Kotzbauer Yuna Ayala Marc I. Diamond Albert A. Davis Conrad Weihl
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The cellular machinery participating in this process is poorly understood. One proteinopathy called multisystem proteinopathy (MSP) is associated with dominant mutations in Valosin Containing Protein (VCP). MSP patients have muscle and neuronal degeneration characterized by aggregate pathology that can include αS, Tau and TDP-43. Methods We performed a fluorescent cell sorting based genome-wide CRISPR-Cas9 screen in αS biosensors. αS and TDP-43 seeding activity under varied conditions was assessed using FRET/Flow biosensor cells or immunofluorescence for phosphorylated αS or TDP-43 in primary cultured neurons. We analyzed in vivo seeding activity by immunostaining for phosphorylated αS following intrastriatal injection of αS seeds in control or VCP disease mutation carrying mice. Results One hundred fifty-four genes were identified as suppressors of αS seeding. One suppressor, VCP when chemically or genetically inhibited increased αS seeding in cells and neurons. This was not due to an increase in αS uptake or αS protein levels. MSP-VCP mutation expression increased αS seeding in cells and neurons. Intrastriatal injection of αS preformed fibrils (PFF) into VCP-MSP mutation carrying mice increased phospho αS expression as compared to control mice. Cells stably expressing fluorescently tagged TDP-43 C-terminal fragment FRET pairs (TDP-43 biosensors) generate FRET when seeded with TDP-43 PFF but not monomeric TDP-43. VCP inhibition or MSP-VCP mutant expression increases TDP-43 seeding in TDP-43 biosensors. Similarly, treatment of neurons with TDP-43 PFFs generates high molecular weight insoluble phosphorylated TDP-43 after 5 days. This TDP-43 seed dependent increase in phosphorlyated TDP-43 is further augmented in MSP-VCP mutant expressing neurons. Conclusion Using an unbiased screen, we identified the multifunctional AAA ATPase VCP as a suppressor of αS and TDP-43 aggregate seeding in cells and neurons. VCP facilitates the clearance of damaged lysosomes via lysophagy. We propose that VCP’s surveillance of permeabilized endosomes may protect against the proteopathic spread of pathogenic protein aggregates. The spread of distinct aggregate species may dictate the pleiotropic phenotypes and pathologies in VCP associated MSP.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">CRISPR screen</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Seeding</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Alpha-synuclein</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">TDP-43</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">Frontotemporal dementia</subfield></datafield><datafield tag="653" ind1=" " ind2="0"><subfield code="a">Neurology. 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VCP suppresses proteopathic seeding in neurons

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