Canavan disease and the role of N-acetylaspartate in myelin synthesis

Namboodiri, Aryan M.A.; Arun, Peethambaran; Mathew, Raji; Sambhu, Prasanth A.; Hershfield, Jeremy R.; Moffett, John R.; Madhavarao, Chikkathur N.

doi:10.1016/j.mce.2006.03.016

Cited by 76 publications

(66 citation statements)

References 45 publications

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“…In this regard, we have observed an approximately 80% reduction in free acetate levels in the brains of ASPA −/− mice at the time of peak myelination . For these reasons we have proposed dietary acetate supplementation therapy, for example with glyceryl triacetate (GTA), as a possible treatment for Canavan disease Mathew et al, 2005;Mehta and Namboodiri, 1995;Namboodiri et al, 2006b).…”

Section: Potential Acetate Supplementation Therapy For Canavan Diseasementioning

confidence: 99%

“…Currently there is no effective treatment available for restoring proper myelination and motor function. The pathogenic mechanisms operative in Canavan disease currently remain a matter of debate, but it has been proposed that the etiology involves a lack of NAA-derived acetate, which is required for some portion of myelin lipid synthesis during postnatal axonal myelination (Hagenfeldt et al, 1987;Kirmani et al, 2002;Madhavarao et al, 2005;Mathew et al, 2005;Mehta and Namboodiri, 1995;Namboodiri et al, 2006b;Namboodiri et al, 2006a). Under this hypothesis, infants born with Canavan disease are normal at birth because ASPA activity is not critical until myelin synthesis is dramatically increased shortly after birth.…”

Section: Naa Breakdown and Myelin Lipid Synthesismentioning

confidence: 99%

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N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,214

1,126

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The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous system-specific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal CNS development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered.

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Section: Potential Acetate Supplementation Therapy For Canavan Diseasementioning

confidence: 99%

Section: Naa Breakdown and Myelin Lipid Synthesismentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,214

1,126

View full text Add to dashboard Cite

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“…NAA is released from neurons to the cerebrospinal fluid and then transported to oligodendrocytes (6,7). Although the exact role of NAA in the brain remains a matter of investigations (1,2,(8)(9)(10)(11), it is believed that proper metabolism of this compound in the brain is important for correct development and maintenance of the white matter (12,13).…”

mentioning

confidence: 99%

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease

Bitto

Bingman

Wesenberg

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

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Aspartoacylase catalyzes hydrolysis of N-acetyl-L-aspartate to aspartate and acetate in the vertebrate brain. Deficiency in this activity leads to spongiform degeneration of the white matter of the brain and is the established cause of Canavan disease, a fatal progressive leukodystrophy affecting young children. We present crystal structures of recombinant human and rat aspartoacylase refined to 2.8-and 1.8-Å resolution, respectively. The structures revealed that the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A. The catalytic site of aspartoacylase shows close structural similarity to those of carboxypeptidases despite only 10 -13% sequence identity between these proteins. About 100 C-terminal residues of aspartoacylase form a globular domain with a two-stranded ␤-sheet linker that wraps around the N-terminal domain. The long channel leading to the active site is formed by the interface of the N-and C-terminal domains. The C-terminal domain is positioned in a way that prevents productive binding of polypetides in the active site. The structures revealed that residues 158 -164 may undergo a conformational change that results in opening and partial closing of the channel entrance. We hypothesize that the catalytic mechanism of aspartoacylase is closely analogous to that of carboxypeptidases. We identify residues involved in zinc coordination, and propose which residues may be involved in substrate binding and catalysis. The structures also provide a structural framework necessary for understanding the deleterious effects of many missense mutations of human aspartoacylase.N-acetyl-L-aspartate ͉ x-ray structure ͉ zinc-dependent hydrolase

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“…Other studies have focused on the "Ac-myelin-lipid" hypothesis and attempted to restore myelination through Ac-supplementation (Arun et al, 2010;Madhavarao et al, 2009;Mathew et al, 2005;Namboodiri et al, 2006;Segel et al, 2011) (Table 2). To this end, calcium Ac (CA) and glyceryl triacetate (GTA) have both been tested in their ability to deliver Ac to the CNS (Mathew et al, 2005;Namboodiri et al, 2006).…”

Section: Supplementation Of Acmentioning

confidence: 99%