Understanding the Ultra-Rare Disease Autosomal Dominant Leukodystrophy: an Updated Review on Morpho-Functional Alterations Found in Experimental Models

Abstract

Autosomal dominant leukodystrophy (ADLD) is an ultra-rare, slowly progressive, and fatal neurodegenerative disorder associated with the loss of white matter in the central nervous system (CNS). Several years after its first clinical description, ADLD was found to be caused by coding and non-coding variants in the LMNB1 gene that cause its overexpression in at least the brain of patients. LMNB1 encodes for Lamin B1, a protein of the nuclear lamina. Lamin B1 regulates many cellular processes such as DNA replication, chromatin organization, and senescence. However, its functions have not been fully characterized yet. Nevertheless, Lamin B1 together with the other lamins that constitute the nuclear lamina has firstly the key role of maintaining the nuclear structure. Being the nucleus a dynamic system subject to both biochemical and mechanical regulation, it is conceivable that changes to its structural homeostasis might translate into functional alterations. Under this light, this review aims at describing the pieces of evidence that to date have been obtained regarding the effects of LMNB1 overexpression on cellular morphology and functionality. Moreover, we suggest that further investigation on ADLD morpho-functional consequences is essential to better understand this complex disease and, possibly, other neurological disorders affecting CNS myelination.

Keywords: ADLD; Cellular Morphology; Cellular Signaling; Demyelination; Lamin B1; Neurodegenerative Diseases; Rare Diseases.

Fig. 1

Schematic representation of ADLD genetic aspects. ADLD is caused by tandem duplications of the LMNB1 gene or by deletions of part of the region located upstream of its promoter. In the tandem duplication variant, an extra copy of LMNB1 is transcripted, while in the upstream deletion variant, it appears that gene expression is enhanced (indicated by the thicker arrow). Therefore, both genetic alterations lead to the over production of the protein Lamin B1, creating a quantitative disproportion between it and the other lamins that constitute the nuclear lamina. Image created with BioRender.com.