Cited by 78Nuclear Structure and FunctionHereditary Neurological DisordersNeurogenesis and neuroplasticity mechanisms

Lamin B1 mediates cell-autonomous neuropathology in a leukodystrophy mouse model

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Heng, Mary Y., Lin, Shu-Ting, Verret, Laure, Huang, Yong, Kamiya, Sherry, Padiath, Quasar S., Tong, Ying, Palop, Jorge J. +3 more·2013·Journal of Clinical Investigation

Abstract

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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Crossref · 10.1172/jci66737

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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
Venue
Journal of Clinical Investigation
Published
2013-05-15
Volume
123
Issue
6
Pages
2719-2729
ISSN
0021-9738 (ISSN-L)
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
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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