TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury
During inflammatory, demyelinating diseases such as multiple sclerosis (MS), inflammation and axonal damage are prevalent early in the course. Axonal damage includes swelling, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise neuro...
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| Format: | Article |
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MDPI AG
2023-06-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/13/1734 |
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| author | Bridget Shafit-Zagardo Simone Sidoli James E. Goldman Juwen C. DuBois John R. Corboy Stephen M. Strittmatter Hillary Guzik Ukuemi Edema Anita G. Arackal Yair M. Botbol Emilio Merheb Rashed M. Nagra Sarah Graff |
| author_facet | Bridget Shafit-Zagardo Simone Sidoli James E. Goldman Juwen C. DuBois John R. Corboy Stephen M. Strittmatter Hillary Guzik Ukuemi Edema Anita G. Arackal Yair M. Botbol Emilio Merheb Rashed M. Nagra Sarah Graff |
| author_sort | Bridget Shafit-Zagardo |
| collection | DOAJ |
| description | During inflammatory, demyelinating diseases such as multiple sclerosis (MS), inflammation and axonal damage are prevalent early in the course. Axonal damage includes swelling, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise neuronal integrity. The clearance of damaged cell components is important to maintain normal turnover and restore homeostasis. In this study, we used mass spectrometry to identify insoluble proteins within high-speed/mercaptoethanol/sarcosyl-insoluble pellets from purified white matter plaques isolated from the brains of individuals with relapsing–remitting MS (RRMS). We determined that the transmembrane protein 106B (TMEM106B), normally lysosome-associated, is insoluble in RRMS plaques relative to normal-appearing white matter from individuals with Alzheimer’s disease and non-neurologic controls. Relative to wild-type mice, hypomorphic mice with a reduction in TMEM106B have increased axonal damage and lipid droplet accumulation in the spinal cord following myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis. Additionally, the corpora callosa from cuprizone-challenged hypomorphic mice fail to clear lipid droplets efficiently during remyelination, suggesting that when TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, further exploration of these sites is warranted. |
| first_indexed | 2024-03-11T01:45:42Z |
| format | Article |
| id | doaj.art-fd1f67f30de94928b8ba0eb64c0dde6f |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T01:45:42Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-fd1f67f30de94928b8ba0eb64c0dde6f2023-11-18T16:19:17ZengMDPI AGCells2073-44092023-06-011213173410.3390/cells12131734TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS InjuryBridget Shafit-Zagardo0Simone Sidoli1James E. Goldman2Juwen C. DuBois3John R. Corboy4Stephen M. Strittmatter5Hillary Guzik6Ukuemi Edema7Anita G. Arackal8Yair M. Botbol9Emilio Merheb10Rashed M. Nagra11Sarah Graff12Department of Pathology, Albert Einstein College of Medicine, New York, NY 10461, USADepartment of Biochemistry, Albert Einstein College of Medicine, New York, NY 10461, USADepartment of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USADepartment of Pathology, Albert Einstein College of Medicine, New York, NY 10461, USARocky Mountain MS Brain Bank, Department of Neurology, University of Colorado School of Medicine, Aurora, CO 80045, USADepartments of Neurology and Neuroscience, Yale School of Medicine, Boyer Center for Molecular Medicine, New Haven, CT 06510, USAAnalytic Imaging Facility, Albert Einstein College of Medicine, New York, NY 10461, USADepartment of Anatomic and Clinical Pathology, Montefiore Medical Center, Bronx, NY 10467, USADepartment of Anatomic and Clinical Pathology, Montefiore Medical Center, Bronx, NY 10467, USADepartment of Pathology, Albert Einstein College of Medicine, New York, NY 10461, USADepartment of Biochemistry, Albert Einstein College of Medicine, New York, NY 10461, USAUCLA Brain Bank, VA Healthcare System, Los Angeles, CA 90073, USADepartment of Biochemistry, Albert Einstein College of Medicine, New York, NY 10461, USADuring inflammatory, demyelinating diseases such as multiple sclerosis (MS), inflammation and axonal damage are prevalent early in the course. Axonal damage includes swelling, defects in transport, and failure to clear damaged intracellular proteins, all of which affect recovery and compromise neuronal integrity. The clearance of damaged cell components is important to maintain normal turnover and restore homeostasis. In this study, we used mass spectrometry to identify insoluble proteins within high-speed/mercaptoethanol/sarcosyl-insoluble pellets from purified white matter plaques isolated from the brains of individuals with relapsing–remitting MS (RRMS). We determined that the transmembrane protein 106B (TMEM106B), normally lysosome-associated, is insoluble in RRMS plaques relative to normal-appearing white matter from individuals with Alzheimer’s disease and non-neurologic controls. Relative to wild-type mice, hypomorphic mice with a reduction in TMEM106B have increased axonal damage and lipid droplet accumulation in the spinal cord following myelin-oligodendrocyte-glycoprotein-induced experimental autoimmune encephalomyelitis. Additionally, the corpora callosa from cuprizone-challenged hypomorphic mice fail to clear lipid droplets efficiently during remyelination, suggesting that when TMEM106B is compromised, protein and lipid clearance by the lysosome is delayed. As TMEM106B contains putative lipid- and LC3-binding sites, further exploration of these sites is warranted.https://www.mdpi.com/2073-4409/12/13/1734multiple sclerosis (MS)TMEM106Bmyelin oligodendrocyte glycoprotein (MOG)-induced EAEdemyelinationlipids |
| spellingShingle | Bridget Shafit-Zagardo Simone Sidoli James E. Goldman Juwen C. DuBois John R. Corboy Stephen M. Strittmatter Hillary Guzik Ukuemi Edema Anita G. Arackal Yair M. Botbol Emilio Merheb Rashed M. Nagra Sarah Graff TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury Cells multiple sclerosis (MS) TMEM106B myelin oligodendrocyte glycoprotein (MOG)-induced EAE demyelination lipids |
| title | TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury |
| title_full | TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury |
| title_fullStr | TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury |
| title_full_unstemmed | TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury |
| title_short | TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury |
| title_sort | tmem106b puncta is increased in multiple sclerosis plaques and reduced protein in mice results in delayed lipid clearance following cns injury |
| topic | multiple sclerosis (MS) TMEM106B myelin oligodendrocyte glycoprotein (MOG)-induced EAE demyelination lipids |
| url | https://www.mdpi.com/2073-4409/12/13/1734 |
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