Altered transcriptional and epigenetic regulation affects brain cells proliferation and differentiation in the ultra-rare genetic demyelinating disease AGC1 deficiency: a study on in vitro models

Poeta, Eleonora (2021) Altered transcriptional and epigenetic regulation affects brain cells proliferation and differentiation in the ultra-rare genetic demyelinating disease AGC1 deficiency: a study on in vitro models, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare, 33 Ciclo.
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Abstract

AGC1 deficiency is a rare demyelinating disease caused by mutations in the SLC25A12 gene, which encodes for the mitochondrial glutamate-aspartate carrier 1 (AGC1/Alarar), highly expressed in the central nervous system. In neurons, impairment in AGC1 activity leads to reduction in N-acetyl-aspartate, the main lipid precursor for myelin synthesis (Profilo et al., 2017); in oligodendrocytes progenitors cells, AGC1 down regulation has been related to early arrest proliferation and premature differentiation (Petralla et al., 2019). Additionally, in vivo AGC1 deficiency models i.e., heterozygous mice for AGC1 knock-out and neurospheres from their subventricular zone, respectively, showed a global decrease in cells proliferation and a switch in neural stem cells (NSCs) commitment, with specific reduction in OPCs number and increase in neural and astrocytic pools (Petralla et al., 2019). Therefore, the present study aims to investigate the transcriptional and epigenetic regulation underlying the alterations observed in OPCs and NSCs biological mechanisms, in either AGC1 deficiency models of Oli-neu cells (murine immortalized oligodendrocytes precursors cells), partially silenced by a shRNA for SLC25A12 gene, and SVZ-derived neurospheres from AGC1+/- mice. Western blot and immunofluorescence analysis revealed significant variations in the expression of transcription factors involved in brain cells’ proliferation and differentiation, in association with altered histone post-translational modifications, as well as histone acetylases (HATs) and deacetylases (HDACs) activity/expression, suggesting an improper transcriptional and epigenetic regulation affecting both AGC1 deficiency in vitro models. Furthermore, given the large role of acetylation in controlling in specific time-windows OPC maturation (Hernandez and Casaccia; 2015), pharmacological HATs/HDACs inhibitions were performed, confirming the involvement of chromatin remodelling enzymes in the altered proliferation and early differentiation observed in the AGC1 deficiency models of siAGC1 Oli-neu cells and AGC1+/- mice-derived neurospheres.

Abstract
Tipologia del documento
Tesi di dottorato
Autore
Poeta, Eleonora
Supervisore
Co-supervisore
Dottorato di ricerca
Ciclo
33
Coordinatore
Settore disciplinare
Settore concorsuale
Parole chiave
White matter disorder, epigenetics, OPCs, NSCs, neurospheres, SLC25A12/AGC1 deficiency
URN:NBN
Data di discussione
20 Ottobre 2021
URI

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