Speaker
Description
"Autosomal Dominant Leukodystrophy (ADLD) is a rare genetic disease associated with white matter loss in the CNS and characterized by autonomic dysfunction and motor impairment. The genetic cause is the presence of three copies of the lamin B1 (LMNB1) gene, which encodes for a structural protein located in the nuclear lamina. Pathogenic mechanisms in ADLD have only initially been explored and a therapy to treat this disease is currently not available.
Based on evidence showing glial pathology in ADLD patients, we generated human glial cells from both ADLD patient- and healthy donor (CTRL)- derived human-induced pluripotent stem cells (hiPSCs), and specifically investigated ADLD astrocytes. Compared to CTRL cells, ADLD astrocytes displayed increased LMNB1 expression, at both RNA and protein level, and morphological and neurochemical cell alterations. Transcriptional profiling of the disease astrocytes pointed to functional defects in a number of key astrocytic functions comprising extracellular matrix composition, calcium signaling and mitochondrial metabolism. The analysis further revealed the acquisition of signs of cellular senescence and abnormalities in RNA processing. Importantly, ADLD Astrocyte Contidioned Medium affects murine and human oligodendrocytes survival and maturation, suggesting a detrimental effect of ADLD astrocytes on oligodendroglia. Moreover, ADLD astrocytes seeded on murine demyelinated organotypic cerebellar cultures have a detrimental effect on the re-myelination process and on myelin maintenance.
Finally, these detrimental effects on oligodendroglia and myelination were successfully reduced by using a specific RNA interference technique called Allele SPecific (ASP) RNAi, which selectively silenced the non-duplicated LMNB1 allele.
Our “disease-in-a-dish” platform reveals previously unknown ADLD astroglial dysfunctions, shedding light on their potential contribution to the white matter loss observed in the disease. Moreover, our results provide direct evidence that ASP RNAi can effectively target and alleviate ADLD pathology in human glial cells."
| Author(s) | Martina Lorenzati*, Marta Ribodino, Arianna Contato, Ersilia Nicorvo, Elena Signorino, Valentina Cerrato, Maryam K. Ardakani, Piercesare Grimaldi, Paola Berchialla, Luciano Conti, Pietro Cortelli, Elisa Giorgio, Annalisa Buffo |
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| Affiliation(s) | "Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi, Department of Sciences of Public Health and Pediatrics - University of Turin (Italy), Department of Clinical and Biological Sciences - University of Turin (Italy), University of Trento (Italy) - Centre for Integrative Biology (CIBIO), Department of Biomedical and Neuromotor Sciences University of Bologna (Italy) - IRCCS Istituto delle Scienze Neurologiche di Bologna, Department of Molecular Medicine University of Pavia (Italy) - IRCCS Mondino Foundation, Department of Neuroscience ""Rita Levi Montalcini"" University of Turin (Italy) - Neuroscience Institute Cavalieri Ottolenghi" |
