LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size
Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been inv...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Serra-Vinardell, Jenny [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2023 |
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| Schlagwörter: |
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| Anmerkung: |
© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 |
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| Übergeordnetes Werk: |
Enthalten in: Cellular and molecular life sciences - Cham (ZG) : Springer International Publishing AG, 1997, 80(2023), 2 vom: 28. Jan. |
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| Übergeordnetes Werk: |
volume:80 ; year:2023 ; number:2 ; day:28 ; month:01 |
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| DOI / URN: |
10.1007/s00018-023-04695-x |
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| Katalog-ID: |
SPR049554131 |
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| 245 | 1 | 0 | |a LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size |
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| 500 | |a © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 | ||
| 520 | |a Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. | ||
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| 650 | 4 | |a iPSC |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Chediak–Higashi syndrome |7 (dpeaa)DE-He213 | |
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| 700 | 1 | |a Sharma, Prashant |0 (orcid)0000-0002-1165-980X |4 aut | |
| 700 | 1 | |a Malicdan, May Christine V. |4 aut | |
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10.1007/s00018-023-04695-x doi (DE-627)SPR049554131 (SPR)s00018-023-04695-x-e DE-627 ger DE-627 rakwb eng Serra-Vinardell, Jenny verfasserin (orcid)0000-0002-2851-6776 aut LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. Autolysosomes (dpeaa)DE-He213 Protolysosomes (dpeaa)DE-He213 Autolysosome tubule (dpeaa)DE-He213 Lysosome fission (dpeaa)DE-He213 iPSC (dpeaa)DE-He213 Chediak–Higashi syndrome (dpeaa)DE-He213 Sandler, Maxwell B. aut De Pace, Raffaella (orcid)0000-0002-8179-6869 aut Manzella-Lapeira, Javier aut Cougnoux, Antony (orcid)0000-0001-9407-7540 aut Keyvanfar, Keyvan aut Introne, Wendy J. aut Brzostowski, Joseph A. (orcid)0000-0003-0257-3905 aut Ward, Michael E. (orcid)0000-0002-5296-8051 aut Gahl, William A. (orcid)0000-0002-2494-6752 aut Sharma, Prashant (orcid)0000-0002-1165-980X aut Malicdan, May Christine V. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 80(2023), 2 vom: 28. Jan. (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:80 year:2023 number:2 day:28 month:01 https://dx.doi.org/10.1007/s00018-023-04695-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 80 2023 2 28 01 |
| spelling |
10.1007/s00018-023-04695-x doi (DE-627)SPR049554131 (SPR)s00018-023-04695-x-e DE-627 ger DE-627 rakwb eng Serra-Vinardell, Jenny verfasserin (orcid)0000-0002-2851-6776 aut LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. Autolysosomes (dpeaa)DE-He213 Protolysosomes (dpeaa)DE-He213 Autolysosome tubule (dpeaa)DE-He213 Lysosome fission (dpeaa)DE-He213 iPSC (dpeaa)DE-He213 Chediak–Higashi syndrome (dpeaa)DE-He213 Sandler, Maxwell B. aut De Pace, Raffaella (orcid)0000-0002-8179-6869 aut Manzella-Lapeira, Javier aut Cougnoux, Antony (orcid)0000-0001-9407-7540 aut Keyvanfar, Keyvan aut Introne, Wendy J. aut Brzostowski, Joseph A. (orcid)0000-0003-0257-3905 aut Ward, Michael E. (orcid)0000-0002-5296-8051 aut Gahl, William A. (orcid)0000-0002-2494-6752 aut Sharma, Prashant (orcid)0000-0002-1165-980X aut Malicdan, May Christine V. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 80(2023), 2 vom: 28. Jan. (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:80 year:2023 number:2 day:28 month:01 https://dx.doi.org/10.1007/s00018-023-04695-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 80 2023 2 28 01 |
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10.1007/s00018-023-04695-x doi (DE-627)SPR049554131 (SPR)s00018-023-04695-x-e DE-627 ger DE-627 rakwb eng Serra-Vinardell, Jenny verfasserin (orcid)0000-0002-2851-6776 aut LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. Autolysosomes (dpeaa)DE-He213 Protolysosomes (dpeaa)DE-He213 Autolysosome tubule (dpeaa)DE-He213 Lysosome fission (dpeaa)DE-He213 iPSC (dpeaa)DE-He213 Chediak–Higashi syndrome (dpeaa)DE-He213 Sandler, Maxwell B. aut De Pace, Raffaella (orcid)0000-0002-8179-6869 aut Manzella-Lapeira, Javier aut Cougnoux, Antony (orcid)0000-0001-9407-7540 aut Keyvanfar, Keyvan aut Introne, Wendy J. aut Brzostowski, Joseph A. (orcid)0000-0003-0257-3905 aut Ward, Michael E. (orcid)0000-0002-5296-8051 aut Gahl, William A. (orcid)0000-0002-2494-6752 aut Sharma, Prashant (orcid)0000-0002-1165-980X aut Malicdan, May Christine V. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 80(2023), 2 vom: 28. Jan. (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:80 year:2023 number:2 day:28 month:01 https://dx.doi.org/10.1007/s00018-023-04695-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 80 2023 2 28 01 |
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10.1007/s00018-023-04695-x doi (DE-627)SPR049554131 (SPR)s00018-023-04695-x-e DE-627 ger DE-627 rakwb eng Serra-Vinardell, Jenny verfasserin (orcid)0000-0002-2851-6776 aut LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. Autolysosomes (dpeaa)DE-He213 Protolysosomes (dpeaa)DE-He213 Autolysosome tubule (dpeaa)DE-He213 Lysosome fission (dpeaa)DE-He213 iPSC (dpeaa)DE-He213 Chediak–Higashi syndrome (dpeaa)DE-He213 Sandler, Maxwell B. aut De Pace, Raffaella (orcid)0000-0002-8179-6869 aut Manzella-Lapeira, Javier aut Cougnoux, Antony (orcid)0000-0001-9407-7540 aut Keyvanfar, Keyvan aut Introne, Wendy J. aut Brzostowski, Joseph A. (orcid)0000-0003-0257-3905 aut Ward, Michael E. (orcid)0000-0002-5296-8051 aut Gahl, William A. (orcid)0000-0002-2494-6752 aut Sharma, Prashant (orcid)0000-0002-1165-980X aut Malicdan, May Christine V. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 80(2023), 2 vom: 28. Jan. (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:80 year:2023 number:2 day:28 month:01 https://dx.doi.org/10.1007/s00018-023-04695-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 80 2023 2 28 01 |
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10.1007/s00018-023-04695-x doi (DE-627)SPR049554131 (SPR)s00018-023-04695-x-e DE-627 ger DE-627 rakwb eng Serra-Vinardell, Jenny verfasserin (orcid)0000-0002-2851-6776 aut LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. Autolysosomes (dpeaa)DE-He213 Protolysosomes (dpeaa)DE-He213 Autolysosome tubule (dpeaa)DE-He213 Lysosome fission (dpeaa)DE-He213 iPSC (dpeaa)DE-He213 Chediak–Higashi syndrome (dpeaa)DE-He213 Sandler, Maxwell B. aut De Pace, Raffaella (orcid)0000-0002-8179-6869 aut Manzella-Lapeira, Javier aut Cougnoux, Antony (orcid)0000-0001-9407-7540 aut Keyvanfar, Keyvan aut Introne, Wendy J. aut Brzostowski, Joseph A. (orcid)0000-0003-0257-3905 aut Ward, Michael E. (orcid)0000-0002-5296-8051 aut Gahl, William A. (orcid)0000-0002-2494-6752 aut Sharma, Prashant (orcid)0000-0002-1165-980X aut Malicdan, May Christine V. aut Enthalten in Cellular and molecular life sciences Cham (ZG) : Springer International Publishing AG, 1997 80(2023), 2 vom: 28. Jan. (DE-627)253390524 (DE-600)1458497-9 1420-9071 nnns volume:80 year:2023 number:2 day:28 month:01 https://dx.doi.org/10.1007/s00018-023-04695-x lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_152 GBV_ILN_161 GBV_ILN_165 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_267 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 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_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4393 GBV_ILN_4700 AR 80 2023 2 28 01 |
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English |
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Enthalten in Cellular and molecular life sciences 80(2023), 2 vom: 28. Jan. volume:80 year:2023 number:2 day:28 month:01 |
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Enthalten in Cellular and molecular life sciences 80(2023), 2 vom: 28. Jan. volume:80 year:2023 number:2 day:28 month:01 |
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Autolysosomes Protolysosomes Autolysosome tubule Lysosome fission iPSC Chediak–Higashi syndrome |
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Cellular and molecular life sciences |
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Serra-Vinardell, Jenny @@aut@@ Sandler, Maxwell B. @@aut@@ De Pace, Raffaella @@aut@@ Manzella-Lapeira, Javier @@aut@@ Cougnoux, Antony @@aut@@ Keyvanfar, Keyvan @@aut@@ Introne, Wendy J. @@aut@@ Brzostowski, Joseph A. @@aut@@ Ward, Michael E. @@aut@@ Gahl, William A. @@aut@@ Sharma, Prashant @@aut@@ Malicdan, May Christine V. @@aut@@ |
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2023-01-28T00:00:00Z |
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Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. 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Serra-Vinardell, Jenny |
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Serra-Vinardell, Jenny misc Autolysosomes misc Protolysosomes misc Autolysosome tubule misc Lysosome fission misc iPSC misc Chediak–Higashi syndrome LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size |
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LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size Autolysosomes (dpeaa)DE-He213 Protolysosomes (dpeaa)DE-He213 Autolysosome tubule (dpeaa)DE-He213 Lysosome fission (dpeaa)DE-He213 iPSC (dpeaa)DE-He213 Chediak–Higashi syndrome (dpeaa)DE-He213 |
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Serra-Vinardell, Jenny Sandler, Maxwell B. De Pace, Raffaella Manzella-Lapeira, Javier Cougnoux, Antony Keyvanfar, Keyvan Introne, Wendy J. Brzostowski, Joseph A. Ward, Michael E. Gahl, William A. Sharma, Prashant Malicdan, May Christine V. |
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Elektronische Aufsätze |
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Serra-Vinardell, Jenny |
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10.1007/s00018-023-04695-x |
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(ORCID)0000-0002-2851-6776 (ORCID)0000-0002-8179-6869 (ORCID)0000-0001-9407-7540 (ORCID)0000-0003-0257-3905 (ORCID)0000-0002-5296-8051 (ORCID)0000-0002-2494-6752 (ORCID)0000-0002-1165-980X |
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(orcid)0000-0002-2851-6776 (orcid)0000-0002-8179-6869 (orcid)0000-0001-9407-7540 (orcid)0000-0003-0257-3905 (orcid)0000-0002-5296-8051 (orcid)0000-0002-2494-6752 (orcid)0000-0002-1165-980X |
| title_sort |
lyst deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size |
| title_auth |
LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size |
| abstract |
Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 |
| abstractGer |
Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 |
| abstract_unstemmed |
Abstract Chediak–Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by biallelic mutations in the lysosomal trafficking regulator (LYST) gene. Even though enlarged lysosomes and/or lysosome-related organelles (LROs) are the typical cellular hallmarks of CHS, they have not been investigated in human neuronal models. Moreover, how and why the loss of LYST function causes a lysosome phenotype in cells has not been elucidated. We report that the LYST-deficient human neuronal model exhibits lysosome depletion accompanied by hyperelongated tubules extruding from enlarged autolysosomes. These results have also been recapitulated in neurons differentiated from CHS patients’ induced pluripotent stem cells (iPSCs), validating our model system. We propose that LYST ensures the correct fission/scission of the autolysosome tubules during autophagic lysosome reformation (ALR), a crucial process to restore the number of free lysosomes after autophagy. We further demonstrate that LYST is recruited to the lysosome membrane, likely to facilitate the fission of autolysosome tubules. Together, our results highlight the key role of LYST in maintaining lysosomal homeostasis following autophagy and suggest that ALR dysregulation is likely associated with the neurodegenerative CHS phenotype. © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023. corrected publication 2023 |
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LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size |
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Sandler, Maxwell B. De Pace, Raffaella Manzella-Lapeira, Javier Cougnoux, Antony Keyvanfar, Keyvan Introne, Wendy J. Brzostowski, Joseph A. Ward, Michael E. Gahl, William A. Sharma, Prashant Malicdan, May Christine V. |
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| score |
7.399419 |