Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease

Gessler, Dominic J.; Li, Danning; Xu, Hongxia; Su, Qin; Sanmiguel, Julio; Tuncer, Serafettin; Moore, Constance M.; King, Jean A.; Matalon, Reuben; Gao, Guangping

doi:10.1172/jci.insight.90807

Cited by 61 publications

(70 citation statements)

References 59 publications

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“…Though early postnatal AAV‐mediated Aspa gene therapy prevents leukodystrophy in CD mice, attempts to translate Aspa gene therapy to infants and children with symptomatic CD have thus far failed to reverse pre‐existing neurological deficits or to prevent disease progression . Neonatal intracerebroventricular administration of an AAV incorporating a short hairpin Nat8l inhibitory RNA to CD mice, which lowered [NAA B ] toward normal, also prevented development of leukodystrophy .…”

Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice

Hull

Wang

Burns

et al. 2020

Annals of Neurology

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Marked elevation in the brain concentration of N‐acetyl‐L‐aspartate (NAA) is a characteristic feature of Canavan disease, a vacuolar leukodystrophy resulting from deficiency of the oligodendroglial NAA‐cleaving enzyme aspartoacylase. We now demonstrate that inhibiting NAA synthesis by intracisternal administration of a locked nucleic acid antisense oligonucleotide to young‐adult aspartoacylase‐deficient mice reverses their pre‐existing ataxia and diminishes cerebellar and thalamic vacuolation and Purkinje cell dendritic atrophy. Ann Neurol 2020;87:480–485

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Section: Discussionmentioning

confidence: 99%

Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice

Hull

Wang

Burns

et al. 2020

Annals of Neurology

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“…We bring attention to a recent study [1] in which a human adeno-associated virus genetic aspartoacylase (ASPA) construct was serendipitously inserted into the "wrong" cell and by redirecting its metabolic processing rescued a murine model of Canavan disease (CD). After achieving an overall cure including enhanced motor performance, these authors were prompted to "hypothesize" that ASPA expression in a non-oligodendrocyte glial cell, astrocytes, might be involved.…”

Section: Rescuing 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%

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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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“…In WM, it was posited that astrocyte‐generated NAA from released NAAG built up in confined, dehydrated and lipid‐rich spaces, which initiated an osmotic hydrostatic condition at nodes of Ranvier and led to the spongiform condition characterized by formation of inter‐sheath vacuoles and the splitting of extant oligodendrocyte myelin sheaths surrounding axons . In support of this hypothesis recent research has shown that redirecting NAA catabolism by insertion of a human ASPA gene‐adenovirus construct into astrocytes—cells that normally do not express this enzyme but that do produce NAA from neuronal NAAG—blocked the buildup of NAA in ECF and rescued CD in a mouse model of the disease …”

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confidence: 99%

Chasing N‐acetyl‐L‐aspartate, a shiny NMR object in the brain

Baslow

2018

NMR in Biomedicine

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N-acetyl-L-aspartate (NAA) is an important NMR object in the mammalian brain almost exclusively present in neurons. It is the most concentrated acetylated amino acid in human brain, at about 10mM, and one of the most concentrated amino acids present in neurons, at about 20mM. NAA has a strong proton MRS signature, at about 2.02 ppm, and is considered to be a specific marker for neuron density and/or viability and an indicator of neuronal loss in many human-brain pathologies. The "NAA' signal is used as a reference point in most brain MRS studies, and its ratio to other brain metabolites, many of which are present in different cells, indicates focal or global brain health in many medical conditions. NAA's high concentration in brain has prompted a search for its function. In 2000, its unique tricellular metabolism was documented. 1 In neurons, NAA is synthesized via NAA synthase 2 from acetyl coenzyme A, derived from the oxidation of glucose (Glc), and L-aspartate (Asp). The dipeptide N-acetylaspartylglutamate (NAAG) is then synthesized from NAA and L-glutamate (Glu) via NAAG synthase 3 ; this is the only known pathway for NAAG synthesis. Both NAA and NAAG turn over every 14 to16 hours, but, remarkably, neither substance can be catabolized by neurons. NAAG is released into extracellular fluid (ECF) and targeted to astrocytes, where it docks with the metabotropic Glu receptor 3 (mGluR3) and is cleaved into Glu and NAA by NAAG peptidase. 4 Astrocytes cannot hydrolyze NAA, so it is released into ECF, taken up by oligodendrocytes, and cleaved into acetate and Asp by aspartoacylase (ASPA), 5 and its products are completely metabolized. 6 While the biochemical pathways in the tricellular metabolism of NAA were already clear, its function and the specific physiological roles of cells in this sequence were not. In Figure 1, the biochemical and metabolic relationships of cells in the tricellular sequence are graphically illustrated. /journal/nbm 1 of 3 and both NAA and NAAG can be exported by neurons via the non-synaptic ATP-binding cassette subfamily C member 5 transporter of Glu conjugates and analogs. 7 mGluR3 is ubiquitous among cell types, and while NAAG can interact with other receptor types only astrocytes express NAAG peptidase, the enzyme that releases Glu from mGluR3-docked NAAG.Second, Canavan disease (CD) is a rare human inborn early-onset spongiform leukodystrophy in which oligodendrocyte ASPA is inactive, so NAA builds to high levels in brain ECF and is excreted in urine. Because NAA is not a neurotransmitter and can readily enter the vascular system for removal, it was proposed that CD was not a GM disease, but a specific WM demyelinating disease. In WM, it was posited that astrocyte-generated NAA from released NAAG built up in confined, dehydrated and lipid-rich spaces, which initiated an osmotic hydrostatic condition at nodes of Ranvier and led to the spongiform condition characterized by formation of inter-sheath vacuoles and the splitting of extant oligodendrocyte myelin sheaths surrounding axons. 13 In ...

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Redirecting N-acetylaspartate metabolism in the central nervous system normalizes myelination and rescues Canavan disease

Cited by 61 publications

References 59 publications

Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice

Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice

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

Chasing N‐acetyl‐L‐aspartate, a shiny NMR object in the brain

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