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.
Highlights
Autosomal-dominant leukodystrophy (ADLD) is an extremely rare, fatal, and late onset progressive neurological disorder which affects the white matter of the central nervous system (CNS) usually, in the IV or V decade [1,2,3].1 3 Vol.:(0123456789)The real prevalence of this ultra-rare pathology remains still uncertain [4] with sporadic new clinical case reports from different geographical areas, suggesting a possible heterogeneity in the first clinical manifestations and signs [5,6,7,8,9,10]
The difference between the ADLD is a rare adult-onset demyelinating neurological disease characterized by Lamin B1 (LMNB1) alterations and with no effective therapies
Recently it has been described that the mRNA level of LMNB1 from peripheral leukocytes of 2 Japanese patients of the same family with upstream deletion was not increased, maybe due to the differences in tissues used for mRNA examination [45]
Summary
Autosomal-dominant leukodystrophy (ADLD) is an extremely rare, fatal, and late onset progressive neurological disorder which affects the white matter of the central nervous system (CNS) usually, in the IV or V decade [1,2,3].1 3 Vol.:(0123456789)The real prevalence of this ultra-rare pathology remains still uncertain [4] with sporadic new clinical case reports from different geographical areas, suggesting a possible heterogeneity in the first clinical manifestations and signs [5,6,7,8,9,10]. Autosomal-dominant leukodystrophy (ADLD) is an extremely rare, fatal, and late onset progressive neurological disorder which affects the white matter of the central nervous system (CNS) usually, in the IV or V decade [1,2,3]. The diagnosis of ADLD is supported by the combination of patient’s clinical history, physical examinations, magnetic resonance imaging (MRI) showing symmetrical cerebral white matter hyperintensities from the motor cortex to the medulla oblongata and involvement of the upper and middle cerebellar peduncles and confirmed by Lamin B1 (LMNB1) gene analysis [1, 13, 16, 18]. The molecular aspects detailing how the genetic alterations affect the cellular mechanisms to drive the onset and development of this pathology are not clear yet. Alterations in the myelin or in the myelination process, or both, due to inflammatory, toxic, or genetic etiology can trigger severe kind of neurological disorders. LIF signaling is triggered by LIF binding to its receptor (LIF-R) that is associated to the transmembrane protein gp130, determining the activation of the Janus kinase–signal transducer and activator of transcription protein 3 (Jak/ Stat3), phosphatidylinositol-3 phosphate kinase (PI3K)/
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