Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

Padiath, Quasar Saleem

doi:10.1080/19491034.2016.1260799

Cited by 14 publications

(20 citation statements)

References 29 publications

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“…ADLD is a rare adult-onset demyelinating neurological disease characterized by LMNB1 alterations and with no effective therapies. The patient phenotype described up to now mainly links the pathology to the overexpression of Lamin B1 protein due to LMNB1 duplication or to LMNB1 upstream deletion [ 44 ]. Nevertheless, 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 ].…”

Section: Discussionmentioning

confidence: 99%

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Ratti

Rusciano

Mongiorgi

et al. 2020

Cell. Mol. Life Sci.

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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.

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Section: Discussionmentioning

confidence: 99%

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Ratti

Rusciano

Mongiorgi

et al. 2020

Cell. Mol. Life Sci.

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“…S8). An abnormal extra copy of LMNB1 gene causes autosomal dominant leukodystrophy (ADLD) characterized by loss of myelin in the brain and the spinal cord, leading to movement problems [48][49][50] . Consistently, we find that LMNB1 expression is obviously increased in DYT1 MNs, and the NE morphology is abnormal at both light-and electron-microscope levels.…”

Section: Increased Nuclear Lmnb1 Causes Abnormal Ne Morphologymentioning

confidence: 99%

Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia

Ding

Tang

et al. 2020

Preprint

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DYT1 dystonia is a hereditary neurological disease caused by a heterozygous mutation in torsin A (TOR1A). While animal models provide insights into disease mechanisms, significant species-dependent differences exist since mice with the identical heterozygous mutation fail to show pathology. Here, we model DYT1 by using human patient-derived motor neurons. These neurons with the heterozygous TOR1A mutation show markedly thickened nuclear lamina, disrupted nuclear morphology, and impaired nucleocytoplasmic transport, whereas they lack the perinuclear blebs that are often observed in animal models. Importantly, we further uncover that the nuclear lamina protein LMNB1 is specifically dysregulated in expression and subcellular localization. LMNB1 downregulation can largely ameliorate all the cellular defects in DYT1 motor neurons. These results reveal the value of disease modeling with human neurons and provide novel molecular mechanisms underlying DYT1 dystonia and potentially other neurological diseases with impaired nucleocytoplasmic transport.

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“…Mouse models engineered to overexpress LMNB1 have proved invaluable in advancing our understanding of the disease ( Padiath, 2016 ). Transgenic mice, where lamin B1 cDNA overexpression was specifically targeted to oligodendrocytes ( Plp-LMNB1 ), the cell types that produce CNS myelin, were normal at birth but exhibited profound age dependent motor dysfunction including ataxia and forelimb paralysis by about 8 months of age, reminiscent of the late age dependent onset of the human disease ( Figure 2A ).…”

Section: Mouse Models Of Adldmentioning

confidence: 99%

Autosomal Dominant Leukodystrophy: A Disease of the Nuclear Lamina

Padiath

2019

Front. Cell Dev. Biol.

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The nuclear lamina is a fibrous meshwork of proteins found adjacent to the inner nuclear membrane that plays a critical role in the maintenance of nuclear architecture. Made up of A and B type lamins, the nuclear lamina has recently been shown to contribute to numerous cellular functions such as chromatin organization, DNA replication, cellular proliferation, senescence, and aging. While at least a dozen disorders are associated with LMNA, the focus of this review is Autosomal Dominant Leukodystrophy (ADLD), the only disease associated with the lamin B1 gene (LMNB1). ADLD is a fatal, adult onset CNS demyelinating disorder that is caused by either genomic duplications involving LMNB1 or deletions upstream of the gene. Both mutation types result in increased LMNB1 gene expression. How the increased levels of this widely expressed nuclear structural component results a phenotype as specific as demyelination is a great mystery. This review summarizes what is currently known about the disease and describes recent work using animal and cell culture models that have provided critical insights into ADLD pathological mechanisms. The delineation of these pathways provides a fascinating glimpse into entirely novel roles for the nuclear lamina and will be critical for the identification of therapies for this fatal disease.

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Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

Cited by 14 publications

References 29 publications

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Cell signaling pathways in autosomal-dominant leukodystrophy (ADLD): the intriguing role of the astrocytes

Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia

Autosomal Dominant Leukodystrophy: A Disease of the Nuclear Lamina

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