The pathogenesis of, and pharmacological treatment for, Canavan disease

Huijun Wei; John R Moffett; Man Amanat; Ali Fatemi; Takashi Tsukamoto; Aryan M Namboodiri; Barbara S Slusher

doi:10.1016/j.drudis.2022.05.019

The pathogenesis of, and pharmacological treatment for, Canavan disease

Drug Discov Today. 2022 Sep;27(9):2467-2483. doi: 10.1016/j.drudis.2022.05.019. Epub 2022 May 27.

Authors

Huijun Wei¹, John R Moffett², Man Amanat³, Ali Fatemi⁴, Takashi Tsukamoto⁵, Aryan M Namboodiri⁶, Barbara S Slusher⁷

Affiliations

¹ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA.
² Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA. Electronic address: john.moffett@usuhs.edu.
³ Kennedy Krieger Institute, Baltimore, MD 21205, USA.
⁴ Department of Neurology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Behavioral Science, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Kennedy Krieger Institute, Baltimore, MD 21205, USA.
⁵ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA.
⁶ Department of Anatomy, Physiology and Genetics and Neuroscience Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.
⁷ Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Neurology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Oncology, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Medicine, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA; Department of Psychiatry, Johns Hopkins University School of Medicine, 855 N. Wolfe Street, Baltimore, MD 21205, USA. Electronic address: bslusher@jhmi.edu.

PMID: 35636725
DOI: 10.1016/j.drudis.2022.05.019

Abstract

Canavan disease (CD) is an inherited leukodystrophy resulting from mutations in the gene encoding aspartoacylase (ASPA). ASPA is highly expressed in oligodendrocytes and catalyzes the cleavage of N-acetylaspartate (NAA) to produce aspartate and acetate. In this review, we examine the pathologies and clinical presentation in CD, the metabolism and transportation of NAA in the brain, and the hypothetical mechanisms whereby ASPA deficiency results in dysmyelination and a failure of normal brain development. We also discuss therapeutic options that could be used for the treatment of CD.

Keywords: Aspartate N-acetyltransferase (Asp-NAT); Aspartoacylase (ASPA); Canavan disease (CD); N-acetylaspartate (NAA); NaDC3.

Publication types

Review
Research Support, N.I.H., Extramural

MeSH terms

Amidohydrolases
Animals
Brain
Canavan Disease*
Disease Models, Animal
Oligodendroglia

Substances

Amidohydrolases