Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis
Open accessAbstract
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS.
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In studies on ALS, loss of crucial BRG1 subunits was found to cause dendritic attrition, which was delayed by overexpressing BRG1.
“In studies on ALS for example, loss of crucial BRG1 subunits was found to cause dendritic attrition, which was delayed by overexpressing BRG1 [152].”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [152]
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Burg, T., Rossaert, E., Moisse, M., Van Damme, P., & Van Den Bosch, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011224 · Cited by 50 · see citing works
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- Authors
- Tibshirani, M., Zhao, B., Gentil, B. J., Minotti, S., Marques, C., Keith, J., Rogaeva, E., Zinman, L., Rouaux, C., Robertson, J., & Durham, H. D.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- University of Toronto (CA)
- Inserm (FR)
- Sunnybrook Health Science Centre (CA)
- Corresponding author
- Durham, Heather D
- ORCID
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-07-26
- Volume
- 26
- Issue
- 21
- Pages
- 4142-4152
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2738143624
- Cited by
- 42
- References
- 48
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 5 · 2019: 5 · 2018: 4
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Amyotrophic Lateral Sclerosis Association
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- amyotrophic lateral sclerosis, chromatin remodeling, SMARCA4, motor neurons, FUS mutations, TDP-43 mutations, familial ALS, dendritic morphology
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Cell Differentiation, Cytoplasm, DNA Helicases, DNA-Binding Proteins, Humans, Motor Neurons, Mutation, Neurons, Nuclear Proteins, Spinal Cord, Transcription Factors, Protein Subunits, RNA-Binding Protein FUS, Chromatin Assembly and Disassembly, Mice
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