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

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

doi:10.3390/cells10102566

Abstract

Autosomal dominant leukodystrophy (ADLD) is an extremely rare and fatal neurodegenerative disease due to the overexpression of the nuclear lamina component Lamin B1. Many aspects of the pathology still remain unrevealed. This work highlights the effect of Lamin B1 accumulation on different cellular functions in an ADLD astrocytic in vitro model. Lamin B1 overexpression induces alterations in cell survival signaling pathways with GSK3β inactivation, but not the upregulation of β-catenin targets, therefore resulting in a reduction in astrocyte survival. Moreover, Lamin B1 build up affects proliferation and cell cycle progression with an increase of PPARγ and p27 and a decrease of Cyclin D1. These events are also associated to a reduction in cell viability and an induction of apoptosis. Interestingly, ADLD astrocytes trigger a tentative activation of survival pathways that are ineffective. Finally, astrocytes overexpressing Lamin B1 show increased immunoreactivity for both GFAP and vimentin together with NF-kB phosphorylation and c-Fos increase, suggesting astrocytes reactivity and substantial cellular activation. These data demonstrate that Lamin B1 accumulation is correlated to biochemical, metabolic, and morphologic remodeling, probably related to the induction of a reactive astrocytes phenotype that could be strictly associated to ADLD pathological mechanisms.

Highlights

Since Lamin B1 build up determines alterations in cell proliferation and cell cycle progression, and results in increased cell death, we investigated the induction of markers of reactive astrocytes
Autosomal dominant leukodystrophy (ADLD) is a rare adult-onset neurodegenerative disorder characterized by LMNB1 alterations and with type no effective
ADLD is a rare adult-onset neurodegenerative disorder characterized by LMNB1 alterations and with no effective therapies

Summary

Introduction

The real prevalence of this fatal pathology still remains uncertain, with sporadic new clinical case reports from different geographical areas suggesting a possible heterogeneity in the first clinical manifestations and signs [4,5,6,7,8,9]. In majority of ADLD cases, the first clinical manifestations are related to autonomic dysfunction, followed by ataxia and cognitive impairment that signal pyramidal and cerebellar involvement. ADLD is characterized by alterations of the LMNB1 gene (chr5q23.2), resulting in the accumulation of Lamin B1, a component of the nuclear lamina [1,8,10]. Demyelination seems to be one of the most significant aspects of ADLD, even if the molecular aspects detailing how the genetic alterations affect the cellular mechanisms to drive the onset and development of this pathology are still not entirely known. Oligodendrocyte cells are certainly the primary cells responsible for the myelination of the axons [11], but signals deriving from astrocytes and neurons are essential to promote myelin sheath formation and its maintenance during life [12]

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