Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model.

Abstract

Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAAB]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. We now report that brain Nat8l knockdown elicited by intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying a short hairpin Nat8l inhibitory RNA to neonatal aspartoacylase-deficient AspaNur7/Nur7 mice lowers [NAAB] and suppresses development of spongiform leukodystrophy.

• Authors: Peter Bannerman, Fuzheng Guo, Olga Chechneva, Travis Burns, Xiaoqing Zhu, Yan Wang, Bokyung Kim, Naveen K Singhal, Jennifer A McDonough, David Pleasure
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 3 Pg. 793-800 (03 07 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 29456021 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• RNA, Messenger
• Acetyltransferases
• Shati protein, mouse
• Amidohydrolases
• aspartoacylase

Topics

• Acetyltransferases (genetics)
• Amidohydrolases (deficiency)
• Animals
• Brain (metabolism, pathology)
• Canavan Disease (genetics, metabolism, pathology, physiopathology)
• Dependovirus (genetics)
• Disease Models, Animal
• Gene Expression
• Gene Knockdown Techniques
• Genetic Vectors (administration & dosage, genetics)
• Mice
• Mice, Knockout
• Motor Activity
• Neurons (metabolism)
• RNA, Messenger (genetics)
• Transduction, Genetic