Back to Search
Start Over
Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes
- Source :
- Cellular and Molecular Life Sciences
- Publication Year :
- 2021
-
Abstract
- Autosomal-dominant leukodystrophy (ADLD) is a rare fatal neurodegenerative disorder with overexpression of the nuclear lamina component, Lamin B1 due to LMNB1 gene duplication or deletions upstream of the gene. The molecular mechanisms responsible for driving the onset and development of this pathology are not clear yet. Vacuolar demyelination seems to be one of the most significant histopathological observations of ADLD. Considering the role of oligodendrocytes, astrocytes, and leukemia inhibitory factor (LIF)-activated signaling pathways in the myelination processes, this work aims to analyze the specific alterations in different cell populations from patients with LMNB1 duplications and engineered cellular models overexpressing Lamin B1 protein. Our results point out, for the first time, that astrocytes may be pivotal in the evolution of the disease. Indeed, cells from ADLD patients and astrocytes overexpressing LMNB1 show severe ultrastructural nuclear alterations, not present in oligodendrocytes overexpressing LMNB1. Moreover, the accumulation of Lamin B1 in astrocytes induces a reduction in LIF and in LIF-Receptor (LIF-R) levels with a consequential decrease in LIF secretion. Therefore, in both our cellular models, Jak/Stat3 and PI3K/Akt axes, downstream of LIF/LIF-R, are downregulated. Significantly, the administration of exogenous LIF can partially reverse the toxic effects induced by Lamin B1 accumulation with differences between astrocytes and oligodendrocytes, highlighting that LMNB1 overexpression drastically affects astrocytic function reducing their fundamental support to oligodendrocytes in the myelination process. In addition, inflammation has also been investigated, showing an increased activation in ADLD patients’ cells.
- Subjects :
- 0301 basic medicine
Cell signaling
Receptors, OSM-LIF
Down-Regulation
Leukemia Inhibitory Factor
03 medical and health sciences
Cellular and Molecular Neuroscience
Phosphatidylinositol 3-Kinases
0302 clinical medicine
ADLD
Cellular signaling
medicine
Humans
Lamin B1
Phosphorylation
STAT3
Molecular Biology
PI3K/AKT/mTOR pathway
Cells, Cultured
Pharmacology
Cell Nucleus
biology
Lamin Type B
LIF
Leukodystrophy
Cell Biology
Hydrogen Peroxide
Fibroblasts
medicine.disease
Cell biology
Up-Regulation
Oligodendroglia
030104 developmental biology
medicine.anatomical_structure
Astrocytes
embryonic structures
biology.protein
Molecular Medicine
Nuclear lamina
Original Article
Inflammation Mediators
Reactive Oxygen Species
Astrocyte
Leukemia inhibitory factor
030217 neurology & neurosurgery
Lamin
Demyelinating Diseases
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cellular and Molecular Life Sciences
- Accession number :
- edsair.doi.dedup.....892b384aecbc3143fd95a899bb9f95da