N -Acetylaspartate and N -acetylaspartylglutamate

Abstract

N -Acetylaspartate (NAA) and its derivative, N -acetylaspartylglutamate (NAAG), are synthesized in neurons and present in very high concentrations in the CNS. NAA is a marker of the functional integrity of neuronal mitochondrial metabolism and may be critical for myelinogenesis,1 whereas NAAG modulates glutamatergic transmission and may have a role in neuroprotection and synaptic plasticity.2 Regional reduction of NAA levels measured by magnetic resonance spectroscopy (MRS) has been used as a marker of neuronal or axonal loss in several neurologic disorders, including traumatic brain injury, stroke, epilepsy, and multiple sclerosis, but may also reflect reversible metabolic impairment. Elevation of NAA levels is a hallmark of Canavan disease, a severe demyelinating disorder of infancy.1 Inhibitors of NAAG peptidase provide neuroprotection in experimental models of stroke, head trauma, and amyotrophic lateral sclerosis (ALS), presumably by increasing endogenous NAAG signaling.2 Thus, elucidation of the neurobiology of NAA and NAAG provides insight into the role of these molecules in the pathophysiology of several neurologic disorders and their potential as a therapeutic target for these conditions. NAA and NAAG participate in important mechanisms of signaling among neurons and glial cells (figure). Figure Interactions among neurons and glial cells mediated by N -acetylaspartate (NAA) and N -acetylaspartylglutamate (NAAG) In neurons, NAA is synthesized in the mitochondria and is then transported to oligodendrocytes, when it is metabolized by the aspartoacylase (ASPA) to acetate. Acetate serves as a precursor for synthesis of myelin lipids. In neurons, NAA is combined to glutamate to produce NAAG, which is released from synaptic vesicles and acts as a cotransmitter with several other neurotransmitters, including l-glutamate. NAAG, acting via presynaptic type 3 metabotropic glutamate receptors (mGluR3), blocks presynaptic calcium (Ca2+) channels, thus inhibiting glutamate release. NAAG may also bind to N -methyl-d-aspartate receptors, blocking their function. NAAG, …