title: Lack of aspartoacylase activity disrupts survival and differentiation of neural progenitors and oligodendrocytes in a mouse model of Canavan disease.
abstract: Loss of the oligodendrocyte (OL)-specific enzyme aspartoacylase (ASPA) from gene mutation results in the sponginess and loss of white matter (WM) in Canavan disease (CD). This study addresses the fate of OLs during the pathophysiology of CD in an adult ASPA knockout (KO) mouse strain. Massive arrays of neural stem/progenitor cells, immunopositive for PSA-NCAM, nestin, vimentin, and NG2, were observed within the severely affected spongy WM of the KO mouse brain. In these mice, G1-->S cell cycle progression was confirmed by an increase in cdk2-kinase activity, a reduction in mitotic inhibitors p21(Cip1) and p27(Kip1), and an increase in bromodeoxyuridine (BrdU) incorporation. Highly acetylated nuclear histones H2B and H3 were detected in adult KO mouse WM, suggesting the existence of noncompact chromatin as seen during early development. Costaining for BrdU- or Ki67-positive cells with markers for neural progenitors confirmed a continuous generation of OL lineage cells in KO WM. We observed a severe reduction in 21.5- and 18.5-kDa myelin basic protein and PLP/DM20 proteolipid proteins combined with a decrease in myelinated fibers and a perinuclear retention of myelin protein staining, indicating impairment in protein trafficking. Death of OLs, neurons, and astrocytes was identified in every region of the KO brain. Immature OLs constituted the largest population of dying cells, particularly in WM. We also report an early expression of full-length ASPA mRNA in normal mouse brain at embryonic day 12.5, when OL progenitors first appear during development. These findings support involvement of ASPA in CNS development and function.
authors.affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Shalini
authors.initials: S
authors.lastname: Kumar
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Biancotti
authors.forename: Reuben
authors.initials: R
authors.lastname: Matalon
authors.forename: Jean
authors.initials: J
authors.lastname: de Vellis
mesh_terms: D000581:Amidohydrolases / Q000235:genetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000002:abnormalities* / Q000201:enzymology* / Q000503:physiopathology; D017825:Canavan Disease / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D002453:Cell Cycle / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006657:Histones / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009836:Oligodendroglia / Q000201:enzymology* / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D013234:Stem Cells / Q000201:enzymology* / Q000473:pathology
chemical_list: D015415:Biomarkers; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006657:Histones; D009185:Myelin Proteins; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; C495893:Cdk2 protein, mouse; D051357:Cyclin-Dependent Kinase 2; D000581:Amidohydrolases; C019751:aspartoacylase