Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes

Ratti, Stefano; Rusciano, Isabella; Mongiorgi, Sara; Neri, Irene; Cappellini, Alessandra; Cortelli, Pietro; Suh, Pann‐Ghill; McCubrey, James A.; Cocco, Lucio; Ramazzotti, Giulia

doi:10.3390/cells10102566

Cited by 5 publications

(2 citation statements)

References 43 publications

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“…A link between lamin B1 overexpression and signalling pathway alterations has been recently supported by our last article, reporting that lamin B increase leads to inactivation of glycogen synthase kinase (GSK)3β, but not the upregulation of β-catenin targets and to a reduction of astrocyte survival in vitro [ 52 ]. Interestingly, astrocytes overexpressing lamin B1 show increased immunoreactivity for both GFAP and vimentin together with NF-κB phosphorylation and c-Fos increase, suggesting astrocytes reactivity and substantial cellular activation [ 52 ].…”

Section: Lamin B-related Laminopathiesmentioning

confidence: 97%

The wide and growing range of lamin B-related diseases: from laminopathies to cancer

Evangelisti

Rusciano

Mongiorgi

et al. 2022

Cell. Mol. Life Sci.

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B-type lamins are fundamental components of the nuclear lamina, a complex structure that acts as a scaffold for organization and function of the nucleus. Lamin B1 and B2, the most represented isoforms, are encoded by LMNB1 and LMNB2 gene, respectively. All B-type lamins are synthesized as precursors and undergo sequential post-translational modifications to generate the mature protein. B-type lamins are involved in a wide range of nuclear functions, including DNA replication and repair, regulation of chromatin and nuclear stiffness. Moreover, lamins B1 and B2 regulate several cellular processes, such as tissue development, cell cycle, cellular proliferation, senescence, and DNA damage response. During embryogenesis, B-type lamins are essential for organogenesis, in particular for brain development. As expected from the numerous and pivotal functions of B-type lamins, mutations in their genes or fluctuations in their expression levels are critical for the onset of several diseases. Indeed, a growing range of human disorders have been linked to lamin B1 or B2, increasing the complexity of the group of diseases collectively known as laminopathies. This review highlights the recent findings on the biological role of B-type lamins under physiological or pathological conditions, with a particular emphasis on brain disorders and cancer. Graphical abstract

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Section: Lamin B-related Laminopathiesmentioning

confidence: 97%

The wide and growing range of lamin B-related diseases: from laminopathies to cancer

Evangelisti

Rusciano

Mongiorgi

et al. 2022

Cell. Mol. Life Sci.

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“…Although on the gene level a therapy has been suggested ( Giorgio et al, 2019 ), the mechanisms behind ADLD remain unknown. Recent studies have contributed to the elucidation of the underlying disease mechanisms for targeted therapy toward specific cellular populations and biochemical pathways ( Ratti et al, 2021a , b ). The focus of these studies were astrocytes overexpressing lamin B1, for which it was shown that they contained several nuclear alterations absent from oligodendrocytes overexpressing lamin B1.…”

Section: Lamin B1 In the Aging Brainmentioning

confidence: 99%

Lamin B1 as a key modulator of the developing and aging brain

Koufi,

Neri,

Ramazzotti

et al. 2023

Front. Cell. Neurosci.

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Lamin B1 is an essential protein of the nuclear lamina that plays a crucial role in nuclear function and organization. It has been demonstrated that lamin B1 is essential for organogenesis and particularly brain development. The important role of lamin B1 in physiological brain development and aging has only recently been at the epicenter of attention and is yet to be fully elucidated. Regarding the development of brain, glial cells that have long been considered as supporting cells to neurons have overturned this representation and current findings have displayed their active roles in neurogenesis and cerebral development. Although lamin B1 has increased levels during the differentiation of the brain cells, during aging these levels drop leading to senescent phenotypes and inciting neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. On the other hand, overexpression of lamin B1 leads to the adult-onset neurodegenerative disease known as Autosomal Dominant Leukodystrophy. This review aims at highlighting the importance of balancing lamin B1 levels in glial cells and neurons from brain development to aging.

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Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult‐Onset Demyelinating Leukodystrophy

Dimartino,

Zadorozhna,

Yumiceba

et al. 2024

Annals of Neurology

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ObjectivesWe aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult‐onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus.BackgroundSince the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus.MethodsHigh‐throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed.ResultsWe collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra‐TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain‐specific misexpression due to inter‐TAD deletions or duplications. The inter‐TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology.InterpretationOur study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024

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Lamin B1 Accumulation’s Effects on Autosomal Dominant Leukodystrophy (ADLD): Induction of Reactivity in the Astrocytes

Cited by 5 publications

References 43 publications

The wide and growing range of lamin B-related diseases: from laminopathies to cancer

The wide and growing range of lamin B-related diseases: from laminopathies to cancer

Lamin B1 as a key modulator of the developing and aging brain

Structural Variants at the LMNB1 Locus: Deciphering Pathomechanisms in Autosomal Dominant Adult‐Onset Demyelinating Leukodystrophy

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