Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model

Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase...
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Autor*in:	Gustavo Morrone Parfitt [verfasserIn] Elena Coccia [verfasserIn] Camille Goldman [verfasserIn] Kristen Whitney [verfasserIn] Ricardo Reyes [verfasserIn] Lily Sarrafha [verfasserIn] Ki Hong Nam [verfasserIn] Soha Sohail [verfasserIn] Drew R. Jones [verfasserIn] John F. Crary [verfasserIn] Alban Ordureau [verfasserIn] Joel Blanchard [verfasserIn] Tim Ahfeldt [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2024

Übergeordnetes Werk:	In: Nature Communications - Nature Portfolio, 2016, 15(2024), 1, Seite 17
Übergeordnetes Werk:	volume:15 ; year:2024 ; number:1 ; pages:17

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41467-024-44732-2

Katalog-ID:	DOAJ097655317

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520			\|a Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model.
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allfields	10.1038/s41467-024-44732-2 doi (DE-627)DOAJ097655317 (DE-599)DOAJ445ece7c4baa4fb2866187e8b98ff91d DE-627 ger DE-627 rakwb eng Gustavo Morrone Parfitt verfasserin aut Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model. Science Q Elena Coccia verfasserin aut Camille Goldman verfasserin aut Kristen Whitney verfasserin aut Ricardo Reyes verfasserin aut Lily Sarrafha verfasserin aut Ki Hong Nam verfasserin aut Soha Sohail verfasserin aut Drew R. Jones verfasserin aut John F. Crary verfasserin aut Alban Ordureau verfasserin aut Joel Blanchard verfasserin aut Tim Ahfeldt verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 17 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:17 https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/article/445ece7c4baa4fb2866187e8b98ff91d kostenfrei https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 17
spelling	10.1038/s41467-024-44732-2 doi (DE-627)DOAJ097655317 (DE-599)DOAJ445ece7c4baa4fb2866187e8b98ff91d DE-627 ger DE-627 rakwb eng Gustavo Morrone Parfitt verfasserin aut Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model. Science Q Elena Coccia verfasserin aut Camille Goldman verfasserin aut Kristen Whitney verfasserin aut Ricardo Reyes verfasserin aut Lily Sarrafha verfasserin aut Ki Hong Nam verfasserin aut Soha Sohail verfasserin aut Drew R. Jones verfasserin aut John F. Crary verfasserin aut Alban Ordureau verfasserin aut Joel Blanchard verfasserin aut Tim Ahfeldt verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 17 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:17 https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/article/445ece7c4baa4fb2866187e8b98ff91d kostenfrei https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 17
allfields_unstemmed	10.1038/s41467-024-44732-2 doi (DE-627)DOAJ097655317 (DE-599)DOAJ445ece7c4baa4fb2866187e8b98ff91d DE-627 ger DE-627 rakwb eng Gustavo Morrone Parfitt verfasserin aut Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model. Science Q Elena Coccia verfasserin aut Camille Goldman verfasserin aut Kristen Whitney verfasserin aut Ricardo Reyes verfasserin aut Lily Sarrafha verfasserin aut Ki Hong Nam verfasserin aut Soha Sohail verfasserin aut Drew R. Jones verfasserin aut John F. Crary verfasserin aut Alban Ordureau verfasserin aut Joel Blanchard verfasserin aut Tim Ahfeldt verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 17 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:17 https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/article/445ece7c4baa4fb2866187e8b98ff91d kostenfrei https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 17
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allfieldsSound	10.1038/s41467-024-44732-2 doi (DE-627)DOAJ097655317 (DE-599)DOAJ445ece7c4baa4fb2866187e8b98ff91d DE-627 ger DE-627 rakwb eng Gustavo Morrone Parfitt verfasserin aut Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model 2024 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model. Science Q Elena Coccia verfasserin aut Camille Goldman verfasserin aut Kristen Whitney verfasserin aut Ricardo Reyes verfasserin aut Lily Sarrafha verfasserin aut Ki Hong Nam verfasserin aut Soha Sohail verfasserin aut Drew R. Jones verfasserin aut John F. Crary verfasserin aut Alban Ordureau verfasserin aut Joel Blanchard verfasserin aut Tim Ahfeldt verfasserin aut In Nature Communications Nature Portfolio, 2016 15(2024), 1, Seite 17 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:15 year:2024 number:1 pages:17 https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/article/445ece7c4baa4fb2866187e8b98ff91d kostenfrei https://doi.org/10.1038/s41467-024-44732-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 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_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 15 2024 1 17
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author	Gustavo Morrone Parfitt
spellingShingle	Gustavo Morrone Parfitt misc Science misc Q Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
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topic_title	Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
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title	Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
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title_full	Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
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title_sort	disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset parkinson’s disease model
title_auth	Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
abstract	Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model.
abstractGer	Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model.
abstract_unstemmed	Abstract Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model.
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title_short	Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
url	https://doi.org/10.1038/s41467-024-44732-2 https://doaj.org/article/445ece7c4baa4fb2866187e8b98ff91d https://doaj.org/toc/2041-1723
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