Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model
Lysosomal storage disorders (LSDs) represent 70 inherited metabolic diseases, in most of which neurodegeneration is a devastating manifestation. The CLN1 disease is a fatal neurodegenerative LSD, caused by inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). S-pa...
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Elsevier
2025-06-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125001068 |
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| author | Nisha Plavelil Abhilash P. Appu K.C. Gopal Avisek Mondal Neil Perkins Anil B. Mukherjee |
| author_facet | Nisha Plavelil Abhilash P. Appu K.C. Gopal Avisek Mondal Neil Perkins Anil B. Mukherjee |
| author_sort | Nisha Plavelil |
| collection | DOAJ |
| description | Lysosomal storage disorders (LSDs) represent 70 inherited metabolic diseases, in most of which neurodegeneration is a devastating manifestation. The CLN1 disease is a fatal neurodegenerative LSD, caused by inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). S-palmitoylation, a reversable posttranslational modification by saturated fatty acids (generally palmitate) facilitates endosomal trafficking of many proteins, especially in the brain. While palmitoyl-acyltransferases (called ZDHHCs) catalyze S-palmitoylation, depalmitoylation is mediated by palmitoyl-protein thioesterases (PPTs). We previously reported that in Cln1−/− mice, which mimic human CLN1-disease, endoplasmic reticulum (ER)-stress leads to unfolded protein response (UPR) contributing to neurodegeneration. However, the mechanism underlying ER-stress has remained elusive. The anterograde (ER to Golgi) protein-trafficking is mediated via COPII (coat protein complex II) vesicles, whereas the retrograde transport (Golgi to ER) is mediated by COPI vesicles. We hypothesized that dysregulated anterograde protein-trafficking causing stagnation of proteins in the ER leads to ER-stress in Cln1−/− mice. We found that the levels of five COPII vesicle-associated proteins (i.e. Sar1, Sec23, Sec24, Sec13 and Sec31) are significantly higher in the ER-fractions of cortical tissues from Cln1−/− mice compared with those from their WT littermates. Remarkably, all COPII proteins, except Sec13, undergo S-palmitoylation. Moreover, CLN8, a Batten disease-protein, requires dynamic S-palmitoylation (palmitoylation-depalmitoylation) for ER-Golgi trafficking. Intriguingly, Ppt1-deficiency in Cln1−/− mice impairs ER-Golgi trafficking of Cln8-protein along with several other COPII-associated proteins. We propose that impaired anterograde trafficking causes excessive accumulation of proteins in the ER causing ER-stress and UPR contributing to neurodegeneration in CLN1 disease. |
| format | Article |
| id | doaj-art-bedfd31020db4bf4bfff76a0e3e1d6a0 |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | Neurobiology of Disease |
| spelling | doaj-art-bedfd31020db4bf4bfff76a0e3e1d6a02025-08-20T02:18:24ZengElsevierNeurobiology of Disease1095-953X2025-06-0120910689010.1016/j.nbd.2025.106890Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease modelNisha Plavelil0Abhilash P. Appu1K.C. Gopal2Avisek Mondal3Neil Perkins4Anil B. Mukherjee5Section on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of AmericaSection on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of AmericaSection on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of AmericaSection on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of AmericaBiostatistics and Bioinformatics Branch (HNT72), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, United States of AmericaSection on Developmental Genetics, Division of Translational Medicine, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1830, United States of America; Corresponding author.Lysosomal storage disorders (LSDs) represent 70 inherited metabolic diseases, in most of which neurodegeneration is a devastating manifestation. The CLN1 disease is a fatal neurodegenerative LSD, caused by inactivating mutations in the CLN1 gene encoding palmitoyl-protein thioesterase-1 (PPT1). S-palmitoylation, a reversable posttranslational modification by saturated fatty acids (generally palmitate) facilitates endosomal trafficking of many proteins, especially in the brain. While palmitoyl-acyltransferases (called ZDHHCs) catalyze S-palmitoylation, depalmitoylation is mediated by palmitoyl-protein thioesterases (PPTs). We previously reported that in Cln1−/− mice, which mimic human CLN1-disease, endoplasmic reticulum (ER)-stress leads to unfolded protein response (UPR) contributing to neurodegeneration. However, the mechanism underlying ER-stress has remained elusive. The anterograde (ER to Golgi) protein-trafficking is mediated via COPII (coat protein complex II) vesicles, whereas the retrograde transport (Golgi to ER) is mediated by COPI vesicles. We hypothesized that dysregulated anterograde protein-trafficking causing stagnation of proteins in the ER leads to ER-stress in Cln1−/− mice. We found that the levels of five COPII vesicle-associated proteins (i.e. Sar1, Sec23, Sec24, Sec13 and Sec31) are significantly higher in the ER-fractions of cortical tissues from Cln1−/− mice compared with those from their WT littermates. Remarkably, all COPII proteins, except Sec13, undergo S-palmitoylation. Moreover, CLN8, a Batten disease-protein, requires dynamic S-palmitoylation (palmitoylation-depalmitoylation) for ER-Golgi trafficking. Intriguingly, Ppt1-deficiency in Cln1−/− mice impairs ER-Golgi trafficking of Cln8-protein along with several other COPII-associated proteins. We propose that impaired anterograde trafficking causes excessive accumulation of proteins in the ER causing ER-stress and UPR contributing to neurodegeneration in CLN1 disease.http://www.sciencedirect.com/science/article/pii/S0969996125001068NeurodegenerationLysosomal storage diseaseER-stressUnfolded protein responseCLN1 diseasePalmitoyl-protein thioesterase-1 |
| spellingShingle | Nisha Plavelil Abhilash P. Appu K.C. Gopal Avisek Mondal Neil Perkins Anil B. Mukherjee Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model Neurobiology of Disease Neurodegeneration Lysosomal storage disease ER-stress Unfolded protein response CLN1 disease Palmitoyl-protein thioesterase-1 |
| title | Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model |
| title_full | Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model |
| title_fullStr | Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model |
| title_full_unstemmed | Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model |
| title_short | Defective anterograde protein-trafficking contributes to endoplasmic reticulum-stress in a CLN1 disease model |
| title_sort | defective anterograde protein trafficking contributes to endoplasmic reticulum stress in a cln1 disease model |
| topic | Neurodegeneration Lysosomal storage disease ER-stress Unfolded protein response CLN1 disease Palmitoyl-protein thioesterase-1 |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125001068 |
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