Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model
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Adult-onset autosomal-dominant leukodystrophy (ADLD) is a progressive and fatal neurological disorder characterized by early autonomic dysfunction, cognitive impairment, pyramidal tract and cerebellar dysfunction, and white matter loss in the central nervous system. ADLD is caused by duplication of the LMNB1 gene, which results in increased lamin B1 transcripts and protein expression. How duplication of LMNB1 leads to myelin defects is unknown. To address this question, we developed a mouse model of ADLD that overexpresses lamin B1. These mice exhibited cognitive impairment and epilepsy, followed by age-dependent motor deficits. Selective overexpression of lamin B1 in oligodendrocytes also resulted in marked motor deficits and myelin defects, suggesting these deficits are cell autonomous. Proteomic and genome-wide transcriptome studies indicated that lamin B1 overexpression is associated with downregulation of proteolipid protein, a highly abundant myelin sheath component that was previously linked to another myelin-related disorder, Pelizaeus-Merzbacher disease. Furthermore, we found that lamin B1 overexpression leads to reduced occupancy of Yin Yang 1 transcription factor at the promoter region of proteolipid protein. These studies identify a mechanism by which lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and implicate lamin B1 as an important regulator of myelin formation and maintenance during aging.
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Loss of lamin B1 has been associated with cognitive decline and neurodegenerative pathology.
“Loss of lamin B1 has been associated with cognitive decline and neurodegenerative pathology [20, 56].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [56]
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Dynamic Lamin B1-Gene Association During Oligodendrocyte Progenitor Differentiation
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Do lamin B1 and lamin B2 have redundant functions?
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- Authors
- Heng, M. Y., Lin, S.-T., Verret, L., Huang, Y., Kamiya, S., Padiath, Q. S., Tong, Y., Palop, J. J., Huang, E. J., Ptácχek, L. J., & Fu, Y.-H.
- Affiliations
- University of California, San Francisco (US)
- Centre de Recherches sur la Cognition Animale (FR)
- Howard Hughes Medical Institute (US)
- San Francisco VA Medical Center (US)
- Gladstone Institutes (US)
- Corresponding author
- Fu, Ying-Hui
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-05-15
- Volume
- 123
- Issue
- 6
- Pages
- 2719-2729
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3668844
- OpenAlex
- W2070299769
- Cited by
- 78
- References
- 51
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 3 · 2023: 8 · 2022: 4 · 2021: 5 · 2020: 7 · 2019: 5 · 2018: 5 · 2017: 6 · 2016: 7 · 2015: 6 · 2014: 8 · 2013: 2
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation (0215759, 9871237)
- Howard Hughes Medical Institute
- A.P. Giannini Foundation
- University of Minnesota
- Gladstone Institutes
- Giannini Foundation of Agricultural Economics
- National Institutes of Health (1f32ns066722-01a1)
- National Institute of Neurological Disorders and Stroke (F32 NS066722, F32 NS066722-01A1, NS062733, R01NS062733)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- lamin B1, oligodendrocytes, proteolipid protein, cognitive impairment, epilepsy, motor impairment, white matter loss, myelin maintenance, aging
- MeSH terms
- Animals, Axons, Disease Models, Animal, Humans, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Myelin Sheath, Oligodendroglia, Promoter Regions, Genetic, Protein Binding, Seizures, Myelin Proteolipid Protein, Genetic Predisposition to Disease, Gait Ataxia, Pelizaeus-Merzbacher Disease, Lamin Type B, Rotarod Performance Test, YY1 Transcription Factor, Mice
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