Publication
Title
Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition
Author
Abstract
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HIT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HIT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
Language
English
Source (journal)
Proceedings of the National Academy of Sciences of the United States of America. - Washington, D.C.
AMERICA
Publication
Washington, D.C. : 2018
ISSN
0027-8424 [Print]
1091-6490 [Online]
Volume/pages
115:37(2018), p. E8765-E8774
ISI
000444257200022
Pubmed ID
30150378
Full text (Publisher's DOI)
Full text (open access)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
European project on the characterisation of transgenic rat models for neurodegenerative and psychiatric diseases: automated home cage analyses, live imaging and treatment. (RATstream)
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identification
Creation 08.10.2018
Last edited 26.07.2021
To cite this reference