Cellular signalling and morphological alterations in Autosomal Dominant Leukodystrophy

Autosomal Dominant Leukodystrophy (ADLD) is a neurodegenerative disorder that affects the central nervous system. It is a rare and late onset lethal progressive disorder without any effective treatment up to date. Genetically it is characterized by Lamin B1 gene duplication or deletion upstream the gene but the mechanisms of how the overexpression of a nuclear structural protein leads to such specific symptom as demyelination are still unclear. Considering the pivotal role that glial cells as astrocytes and oligodendrocytes and Leukemia Inhibitory Factor (LIF) have in the myelination process, this work was intended to analyse the morpho-functional aspects of different cell populations, which are engineered cellular models overexpressing Lamin B1 and primary cells deriving from ADLD patients. The results have, to date, highlighted that the astrocytes may be pivotal in the development of the disease. Analysing the cellular ultrastructure, astrocytes overexpressing Lamin B1 show several nuclear alterations similar to the ones observed in cells deriving from ADLD patients, which, on the contrary are not present in oligodendrocytes overexpressing Lamin B1. In addiction astrocytes overexpressing Lamin B1 are not capable to produce LIF and besides the receptor (LIF-R) is downregulated, it is downregulated as well as in oligodendrocytes overexpressing Lamin B1. In both engineered models, the confirmation that this signalling pathway is altered in the cell overexpressing Lamin B1, is given to us by analysing the signalling transduction pathways downstream LIF/LIF-R. In fact, both PI3K/AKT and JAK/STAT3 axes are downregulated but surprisingly with exogenous LIF administration is possible recovered the phenotype. In particular, the toxic effect induced by Lamin B1 accumulation results in the ability of oligodendrocytes, being less affected, to completely recover the phenotype, which instead is only partial for astrocytes. Therefore, this leads us to hypothesize that astrocytes, being severely affected by Lamin B1 accumulation, lose their role of support for the oligodendrocytes in the myelination process. Finally, inflammation and ROS production was also been found in ADLD patients’ cells as alleged in literature in relation to the Lamin B1 accumulation and advancement of age. These new discoveries both as regards cellular, morphological and functional alterations, and as regards the inflammatory process and oxidative stress could pay the way for new avenues of investigation in the ADLD disease.