Aspartoacylase deficiency and N‐acetylaspartic aciduria in patients with canavan disease

Matalon, Reuben; Michals, K.; Sebesta, Donald G.; Deanching, M.; Gashkoff, P.; Casanova, J.

doi:10.1002/ajmg.1320290234

Cited by 381 publications

(250 citation statements)

References 15 publications

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“…They proposed that the observed dysmyelination in the CNS was due to a failure of NAA to serve as an acetate carrier of acetyl groups from mitochondria to cytoplasm for lipogenesis (Hagenfeldt et al, 1987). Matalon and colleagues were the first to connect Nacetylaspartic aciduria and ASPA deficiency specifically to Canavan disease by showing high NAA levels in urine, and a lack of ASPA activity in skin fibroblasts in 3 children with Canavan disease (Matalon et al, 1988). They proposed three possible mechanisms whereby a lack of ASPA activity could lead to the spongy degeneration and dysmyelination observed in Canavan disease patients.…”

Section: Naa and Canavan Diseasementioning

confidence: 99%

“…First was the prominence of the NAA proton signal in magnetic resonance spectroscopy (MRS), making NAA one of the most reliable markers for brain MRS studies (Barany et al, 1987;Fan et al, 1986;Luyten and den Hollander, 1986). The second was the connection to the rare but fatal hereditary genetic disorder known as Canavan disease (Bartalini et al, 1992;Divry and Mathieu, 1989;Hagenfeldt et al, 1987;Matalon et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,230

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 and Canavan Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

Moffett

Ross

Arun

et al. 2007

Progress in Neurobiology

1,230

1,126

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“…ASPA), which catalyzes deacetylation of N-acetyl-L-aspartate (NAA). Typical CD pathology is marked by early onset macrocephaly, head-lag, ataxia, severe psychomotor retardation, brain vacuolization, and dysmyelination resulting in death during childhood, though there are several reports of clinically protracted disease courses (Elpeleg et al 1994,Janson et al 2006,Leone et al 1999,Matalon et al 1988,Shaag et al 1995,Surendran et al 2003a,Tacke et al 2005,Yalcinkaya et al 2005,Zafeiriou et al 1999,Zelnik et al 1993. Considerable effort has been devoted to understanding the basis of CD by elucidating the function of ASPA in the central nervous system (CNS).…”

Section: Introductionmentioning

confidence: 99%

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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“…271900), a fatal progressive neurodegenerative disorder characterized by dysmyelination and spongiform degeneration of white matter in children (19)(20)(21)(22). Clinically, CD is characterized by megalocephaly, hypotonia of neck muscles that results in poor head control, muscle rigidity, developmental delay of motor and verbal skills, visual impairment, and feeding difficulties (20)(21)(22)(23)(24).…”

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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Aspartoacylase deficiency and N‐acetylaspartic aciduria in patients with canavan disease

Cited by 381 publications

References 15 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

Structure of aspartoacylase, the brain enzyme impaired in Canavan disease

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