Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease

Kirmani, Batool F.; Jacobowitz, David M.; Kallarakal, Abraham T.; Namboodiri, M. A. A.

doi:10.1016/s0169-328x(02)00490-4

Cited by 57 publications

(53 citation statements)

References 25 publications

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“…In situ hybridization studies further confirmed that ASPA was present in oligodendrocytes, and that its expression pattern paralleled that of myelination (Kirmani et al, 2002;Kirmani et al, 2003). Immunohistochemical studies using polyclonal antibodies to ASPA confirmed that it was expressed in oligodendrocytes (Klugmann et al, 2003).…”

Section: Naa Catabolismmentioning

confidence: 61%

“…et al, 1973;Kirmani et al, 2003) becomes critical in order to liberate the acetate from NAA for the synthesis of acetyl CoA, which is necessary for the synthesis of certain myelin-associated lipids. A number of studies, including the recent demonstrations of the selective localization of ASPA in oligodendrocytes in the CNS Kirmani et al, 2002;Klugmann et al, 2003;Madhavarao et al, 2004), and the increasing NAA concentrations observed by MRS in human fetuses in utero during development (Girard et al, 2005) are consistent with the acetate-deficiency hypothesis of Canavan disease.…”

Section: Naa Breakdown and Myelin Lipid Synthesismentioning

confidence: 67%

“…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%

“…It had been proposed in the 1970's that NAA synthesis in neuronal mitochondria might be a mechanism for transporting carbon from the mitochondrial matrix to the cytoplasm (Miller et al, 1996;Patel and Clark, 1979), much as citrate does in other cell types (Clark, 1998). However, this proposal was made before the discovery that the NAA degrading enzyme ASPA was not present in neurons, but instead was expressed predominantly in oligodendrocytes Kirmani et al, 2002;Madhavarao et al, 2004). The possibility that one function of NAA is to move acetate carbon units from neuronal mitochondria to the cytoplasm of oligodendrocytes was discussed above in Section 5.1.…”

Section: A Model Of Naa Synthesis Linked To Mitochondrial Energetics mentioning

confidence: 99%

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N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,208

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: Naa Catabolismmentioning

confidence: 61%

Section: Naa Breakdown and Myelin Lipid Synthesismentioning

confidence: 67%

Section: Naa Breakdown and Myelin Lipid Synthesismentioning

confidence: 99%

Section: A Model Of Naa Synthesis Linked To Mitochondrial Energetics mentioning

confidence: 99%

See 2 more Smart Citations

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,208

1,126

View full text Add to dashboard Cite

show abstract

“…Developmental increases in ASPA and NAA correlate with myelination (Burri et al 1991,D'Adamo et al 1973,Kirmani et al 2003 and several studies have shown incorporation of acetate from NAA into myelin lipids (Benuck & D'Adamo 1968,Burri et al 1991,Chakraborty et al 2001,D'Adamo & Yatsu 1966,Mehta & Namboodiri 1995. Total acetate levels and complete myelin lipid synthesis have recently been shown to be deficient in brains of CD knockout mice (Madhavarao et al 2005), providing strong support for the hypothesis that NAA in the CNS supplies acetyl groups for lipid synthesis during myelination (Hagenfeldt et al 1987,Kirmani et al 2002,Kirmani et al 2003,Madhavarao et al 2005,Mehta & Namboodiri 1995. Furthermore, ASPA is found in cells within both cytoplasm and nucleus (Hershfield et al 2006), though its role in the nucleus is yet to be delineated.…”

Section: Introductionmentioning

confidence: 91%

Mutational analysis of aspartoacylase: Implications for Canavan Disease

et al. 2007

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Mutations that result in undetectable activity of aspartoacylase, which catalyzes the deacetylation of N-acetyl-L-aspartate, correlate with Canavan Disease, a neurodegenerative disorder usually fatal during childhood. The underlying biochemical mechanisms of how these mutations ablate activity are poorly understood. Therefore, we developed and tested a three-dimensional homology model of aspartoacylase based on zinc dependent carboxypeptidase A. Mutations of the putative zinc-binding residues (H21G, E24D/G, and H116G), the general proton donor (E178A), and mutants designed to switch the order of the zinc-binding residues (H21E/E24H and E24H/H116E) yielded wild-type aspartoacylase protein levels and undetectable ASPA activity. Mutations that affect substrate carboxyl binding (R71N) and transition state stabilization (R63N) also yielded wild-type aspartoacylase protein levels and undetectable aspartoacylase activity. Alanine substitutions of Cys124 and Cys152, residues indicated by homology modeling to be in close proximity and in the proper orientation for disulfide bonding, yielded reduced ASPA protein and activity levels. Finally, expression of several previously tested (E24G, D68A, C152W, E214X, D249V, E285A, and A305E) and untested (H21P, A57T, I143T, P183H, M195R, K213E/G274R, G274R, and F295S) Canavan Disease mutations resulted in undetectable enzyme activity, and only E285A and P183H showed wild-type aspartoacylase protein levels. These results show that aspartoacylase is a member of the caboxypeptidase A family and offer novel explanations for most loss-of-function aspartoacylase mutations associated with Canavan Disease.

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Genetic disorders associated with macrocephaly

Williams

Dagli

Battaglia

2008

American J of Med Genetics Pt A

123

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Macrocephaly is associated with many genetic disorders and is a frequent cause of referral to the clinical geneticist. In this review we classify the commonly encountered macrocephaly disorders into useful categories and summarize recent genetic advances. Conditions where macrocephaly is a predominant aspect of the clinical presentation are discussed and a diagnostic approach to the common macrocephaly disorders is provided. Some emphasis is placed on familial macrocephaly (sometimes referred to as benign external hydrocephalus) and on the macrocephaly associated with autism spectrum disorders. The more recent conditions associated with the leukodystrophies and the organic acidurias are reviewed, but the well known conditions involving storage disorders and bone dysplasias are mentioned but not discussed. The genetic macrocephaly conditions cover a broad spectrum of gene disorders and their related proteins have diverse biological functions. As of yet it is not clear what precise biological pathways lead to generalized brain overgrowth. ß

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Aspartoacylase is restricted primarily to myelin synthesizing cells in the CNS: therapeutic implications for Canavan disease

Cited by 57 publications

References 25 publications

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Mutational analysis of aspartoacylase: Implications for Canavan Disease

Genetic disorders associated with macrocephaly

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