Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

Mendes, Marisa I.; Smith, Desirée E.C.; Pop, Ana; Lennertz, Pascal; Ojeda, Matilde R. Fernandez; Kanhai, Warsha A.; Dooren, Silvy J.M. van; Anikster, Yair; Barić, Ivo; Boelen, Caroline; Campistol, J; Boer, Lonneke de; Kariminejad, Ariana; Kayserili, Hülya; Roubertie, Agathe; Verbruggen, Krijn T.; Vianey‐Saban, Christine; Williams, Monique J.; Salomons, Gajja S.

doi:10.1002/humu.23181

Cited by 23 publications

(26 citation statements)

References 39 publications

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“…Although disputed, it appears that the deficiency of acetate, which is necessary for correct myelin formation, is the etiological mechanism of Canavan disease, rather than the excess of NAA [16,20]. Canavan disease is prevalent among the Ashkenazi Jewish population and the two most frequent mutations in the ASPA gene (c.854A>C; p.E285A and c.914C>A; p.A305E) both result in low, but detectable residual enzyme activity [21][22][23]. Even minor differences in residual enzyme activity may be important in determining disease severity [22,23].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Canavan disease is prevalent among the Ashkenazi Jewish population and the two most frequent mutations in the ASPA gene (c.854A>C; p.E285A and c.914C>A; p.A305E) both result in low, but detectable residual enzyme activity [21][22][23]. Even minor differences in residual enzyme activity may be important in determining disease severity [22,23].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…compromised myelination as one of the major features due to impaired activity of the ASPA enzyme [75]. To date, more than 100 ASPA mutations have been described, and the most prevalent result in low levels of residual activity of the enzyme (http://www.lovd.nl/ASPA) [21][22][23]76]. In a recent study, Mendes et al showed that there is a correlation between ASPA residual activity and disease severity in Canavan disease.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Dembić

Andersen

Bastin

et al. 2019

Molecular Genetics and Metabolism

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Resveratrol (RSV) is a small compound first identified as an activator of sirtuin 1 (SIRT1), a key factor in mediating the effects of caloric restriction. Since then, RSV received great attention for its widespread beneficial effects on health and in connection to many diseases. RSV improves the metabolism and the mitochondrial function, and more recently it was shown to restore fatty acid βoxidation (FAO) capacities in patient fibroblasts harboring mutations with residual enzyme activity. Many of RSV's beneficial effects are mediated by the transcriptional coactivator PGC-1α, a direct target of SIRT1 and a master regulator of the mitochondrial fatty acid oxidation. Despite numerous studies RSV's mechanism of action is still not completely elucidated. Our aim was to investigate the effects of RSV on gene regulation on a wide scale, possibly to detect novel genes whose upregulation by RSV may be of interest with respect to disease treatment. We performed Next Generation Sequencing of RNA on normal fibroblasts treated with RSV. To investigate whether the effects of RSV are mediated through SIRT1 we expanded the analysis to include SIRT1knockdown fibroblasts. We identified the aspartoacylase (ASPA) gene, mutated in Canavan disease, to be strongly up-regulated by RSV in several cell lines, including Canavan disease fibroblasts. We further link RSV to the up-regulation of other genes involved in myelination including the glial specific transcription factors POU3F1, POU3F2, and myelin basic protein (MBP). We also observe a strong up-regulation by RSV of the riboflavin transporter gene SLC52a1. Mutations in SLC52a1 cause transient multiple acyl-CoA dehydrogenase deficiency (MADD). Our analysis of alternative splicing identified novel metabolically important genes affected by RSV, among which is particularly interesting the α subunit of the stimulatory G protein (Gsα), which regulates the cellular levels of cAMP through adenylyl cyclase. We conclude that in fibroblasts RSV stimulates the PGC-1α and p53 pathways, and up-regulates genes affecting the glucose metabolism, mitochondrial β-oxidation, and mitochondrial biogenesis. We further confirm that RSV might be a relevant treatment in the correction of FAO deficiencies and we suggest that treatment in other metabolic disorders including Canavan disease and MADD might be also beneficial.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

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Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Dembić

Andersen

Bastin

et al. 2019

Molecular Genetics and Metabolism

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“…Children with CD may appear relatively normal at birth but fail to reach typical milestones in development. An early subjective sign is the loss of These cases, although imperfectly associated with the amount of residual activity of the ASPA enzyme protein [3], are highly significant in that they show (1) that an elevated level of NAA in whole brain by itself does not cause CD, and (2) that a small amount of residual ASPA activity (<1 to 12.4 %) may rescue CD. The imperfect association between residual ASPA protein activity and mild cases of human CD may be explained by the presence of a second non-specific acylase that has been observed to be expressed by cultured rat astrocytes and that has some activity against NAA [5].…”

Section: The Nature Of Canavan Diseasementioning

confidence: 99%

“…CD is an autosomal recessive disease due to inborn errors resulting from more than 100 different mutations in which oligodendrocyte expressed ASPA is inactive [1,2,3]. CD is a rare disease in that there are only several hundred human cases worldwide at any given time.…”

Section: The Nature Of Canavan Diseasementioning

confidence: 99%

Rescuing Canavan Disease: Support For The Astrocyte Hypothesis Of Canavan Disease Generation And A Possible Human Cure.

Baslow

Guilfoyle

2017

JGM

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Canavan disease (CD) is a globally occurring but rare human spongiform leukodystrophy that is associated with inborn errors affecting the activity of aspartoacylase (ASPA), an enzyme highly expressed in oligodendrocytes that hydrolyzes N-acetylaspartate (NAA). Lack of ASPA activity is associated with the inability of oligodendrocytes to build or maintain axon-enveloping myelin sheaths. The primary source of NAA in brain is neurons, cells that synthesize but cannot catabolize it. Neurons also synthesize N-acetylaspartylglutamate (NAAG) from NAA and glutamate but cannot catabolize this substance as well. For their metabolism, these substances are released to extracellular fluid and are metabolized by oligodendrocyte ASPA and astrocyte NAAG peptidase respectively. A hypothesis developed suggested that the cause of the leukodystrophy component in CD was due to release of NAAG by neurons at white matter nodes of Ranvier, its catabolism by astrocytes forming NAA and increased osmotic-hydrostatic pressure as a result of its buildup at these nodes due to the lack of ASPA activity. In this communication, we provide evidence supporting this hypothesis and comment on the cause and possible cure for human CD.

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Pathological Bergmann glia alterations and disrupted calcium dynamics in ataxic Canavan disease mice

Hull,

Wang,

Burns

et al. 2023

Glia

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Canavan disease (CD) is a recessively inherited pediatric leukodystrophy resulting from inactivating mutations to the oligodendroglial enzyme aspartoacylase (ASPA). ASPA is responsible for hydrolyzing the amino acid derivative N‐acetyl‐L‐aspartate (NAA), and without it, brain NAA concentrations increase by 50% or more. Infants and children with CD present with progressive cognitive and motor delays, cytotoxic edema, astroglial vacuolation, and prominent spongiform brain degeneration. ASPA‐deficient CD mice (Aspanur7/nur7) present similarly with elevated NAA, widespread astroglial dysfunction, ataxia, and Purkinje cell (PC) dendritic atrophy. Bergmann glia (BG), radial astrocytes essential for cerebellar development, are intimately intertwined with PCs, where they regulate synapse stability, functionality, and plasticity. BG damage is common to many neurodegenerative conditions and frequently associated with PC dysfunction and ataxia. Here, we report that, in CD mice, BG exhibit significant morphological alterations, decreased structural associations with PCs, loss of synaptic support proteins, and altered calcium dynamics. We also find that BG dysfunction predates cerebellar vacuolation and PC damage in CD mice. Previously, we developed an antisense oligonucleotide (ASO) therapy targeting Nat8l (N‐acetyltransferase‐8‐like, “Nat8l ASO”) that inhibits the production of NAA and reverses ataxia and PC atrophy in CD mice. Here, we show that Nat8l ASO administration in adult CD mice also leads to BG repair. Furthermore, blocking astroglial uptake of NAA is neuroprotective in astroglia‐neuron cocultures exposed to elevated NAA. Our findings suggest that restoration of BG structural and functional integrity could be a mechanism for PC regeneration and improved motor function.

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Clinically Distinct Phenotypes of Canavan Disease Correlate with Residual Aspartoacylase Enzyme Activity

Cited by 23 publications

References 39 publications

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Rescuing Canavan Disease: Support For The Astrocyte Hypothesis Of Canavan Disease Generation And A Possible Human Cure.

Pathological Bergmann glia alterations and disrupted calcium dynamics in ataxic Canavan disease mice

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