Brain Nat8I Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model

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

来源：Molecular Therapy, 2018, 26(3): 793-800.

DOI：10.1016/j.ymthe.2018.01.002

• ACETYL-L-ASPARTATE
• ADENOASSOCIATED VIRUS VECTORS
• SYSTEM VAN-BOGAERT
• N-ACETYLASPARTATE
• SPONGY DEGENERATION
• LIPID-SYNTHESIS
• GENE-THERAPY
• MYELIN
• PATHOLOGY
• TOXICITY

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 ([NAA(B)]). 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 ASpa(Nur7/Nur7) mice lowers [NAA(B)] and suppresses development of spongiform leukodystrophy.

• 出版日期2018-3-7
• 单位青岛大学