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

Peter Bannerman, Fuzheng Guo, Olga Chechneva, Travis Burns, Xiaoqing Zhu, Yan Wang, Bokyung Kim, Naveen K. Singhal, Jennifer A. McDonough, David E Pleasure

Research output: Contribution to journalArticle

2 Citations (Scopus)

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. Prior studies demonstrated that constitutive Nat8l knockout prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. Bannerman et al. now report that neonatal intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying an Nat8l inhibitory short hairpin RNA preserves motor function and suppresses spongiform leukodystrophy in 3-month-old aspartoacylase-deficient mice.

Original languageEnglish (US)
Pages (from-to)793-800
Number of pages8
JournalMolecular Therapy
Volume26
Issue number3
DOIs
StatePublished - Mar 7 2018

Fingerprint

Canavan Disease
Brain
Gene Knockout Techniques
Acetyltransferases
Enzymes
aspartoacylase
Aspartic Acid
Small Interfering RNA
Acetates
RNA
Amino Acids
Mutation

Keywords

  • Canavan disease
  • leukodystrophy
  • Nat8l knockdown

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model. / Bannerman, Peter; Guo, Fuzheng; Chechneva, Olga; Burns, Travis; Zhu, Xiaoqing; Wang, Yan; Kim, Bokyung; Singhal, Naveen K.; McDonough, Jennifer A.; Pleasure, David E.

In: Molecular Therapy, Vol. 26, No. 3, 07.03.2018, p. 793-800.

Research output: Contribution to journalArticle

Bannerman, Peter ; Guo, Fuzheng ; Chechneva, Olga ; Burns, Travis ; Zhu, Xiaoqing ; Wang, Yan ; Kim, Bokyung ; Singhal, Naveen K. ; McDonough, Jennifer A. ; Pleasure, David E. / Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model. In: Molecular Therapy. 2018 ; Vol. 26, No. 3. pp. 793-800.
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