Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition

Zink, Caroline F.; Barker, Peter B.; Sawa, Akira; Weinberger, Daniel R.; Wang, Min; Quillian, Henry M.; Ulrich, William; Chen, Qiang; Jaffe, Andrew E.; Kleinman, Joel E.; Hyde, Thomas M.; Prettyman, Greer; Giegerich, Mellissa; Carta, Kayla; Ginkel, Marcus van; Bigos, Kristin L.

doi:10.1176/appi.ajp.2020.19111152

Cited by 35 publications

(36 citation statements)

References 67 publications

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“…Several studies indicated that NAAG plays a role in long term as well as short term/working memory (for review: Neale & Olszewski, 2019). A role of NAAG in the latter is suggested by a recent study that identified GCPII mutation in humans that led to higher enzymatic activity and therefore reduced NAAG levels and is associated with deficits in working memory (Zink et al., 2020). Furthermore, Shati/Nat8l −/− mice are impaired in an object‐based attention test (Wulaer et al, 2020), though it is unclear whether this results from deficiency in NAAG or its precursor NAA, which both are reduced in Nat8l −/− mice.…”

Section: Discussionmentioning

confidence: 99%

“…A role of NAAG in the latter is suggested by a recent study that identified GCPII mutation in humans that led to higher enzymatic activity and therefore reduced NAAG levels and is associated with deficits in working memory (Zink et al, 2020). Furthermore, Shati/Nat8l −/− mice are impaired in an object-based attention test (Wulaer et al, 2020) (Adedoyin et al, 2010;Lea et al, 2001), there are several reports indicating a procognitive role of NAAG in long-term memory.…”

Section: F I G U R Ementioning

confidence: 99%

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Mice deficient in the NAAG synthetase II gene Rimkla are impaired in a novel object recognition task

Becker

Wang-Eckhardt

Lodder-Gadaczek

et al. 2021

Journal of Neurochemistry

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N‐acetylaspartylglutamate (NAAG) is an abundant neuropeptide in the mammalian nervous system, synthesized by two related NAAG synthetases I and II (NAAGS‐I and ‐II) encoded by the genes Rimklb and Rimkla, respectively. NAAG plays a role in cognition and memory, according to studies using inhibitors of the NAAG hydrolase glutamate carboxypeptidase II that increase NAAG concentration. To examine consequences of reduced NAAG concentration, Rimkla‐deficient (Rimkla−/−) mice were generated. These mice exhibit normal NAAG level at birth, likely because of the intact Rimklb gene, but have significantly reduced NAAG levels in all brain regions in adulthood. In wild type mice NAAGS‐II was most abundant in brainstem and spinal cord, as demonstrated using a new NAAGS‐II antiserum. In the hippocampus, NAAGS‐II was only detectable in neurons expressing parvalbumin, a marker of GABAergic interneurons. Apart from reduced open field activity, general behavior of adult (6 months old) Rimkla−/− mice examined in different tests (dark‐light transition, optokinetic behavior, rotarod, and alternating T‐maze) was not significantly altered. However, Rimkla−/− mice were impaired in a short‐term novel object recognition test. This was also the case for mice lacking NAA synthase Nat8l, which are devoid of NAAG. Together with results from previous studies showing that inhibition of the NAAG degrading enzyme glutamate carboxypeptidase II is associated with a significant improvement in object recognition, these results suggest a direct involvement of NAAG synthesized by NAAGS‐II in the memory consolidation underlying the novel object recognition task.

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Section: Discussionmentioning

confidence: 99%

Section: F I G U R Ementioning

confidence: 99%

Mice deficient in the NAAG synthetase II gene Rimkla are impaired in a novel object recognition task

Becker

Wang-Eckhardt

Lodder-Gadaczek

et al. 2021

Journal of Neurochemistry

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“…In addition, the reduced brain NAAG levels were directly associated with worse cognitive performance. Furthermore, patients with the missense mutation had higher levels of cortical activity during tasks of working memory, indicating that their brains had to work harder to complete the tasks [53]. This work underscores the importance of GCPII and NAAG in regulating cognitive function in both healthy individuals and those with neurological diseases.…”

Section: Discussionmentioning

confidence: 66%

“…Inhibition of GCPII activity has demonstrated benefit in a host of preclinical studies, including models of schizophrenia, Alzheimer's disease, ethanol intoxication, and pain [51,52], in addition to MS [8,9]. A recent study provided more mechanistic evidence for a role of GCPII and NAAG in cognitive function [53]. A missense mutation in the FOLH1 gene that codes for GCPII (rs202676) was found to be associated with both increased GCPII expression and decreased brain NAAG levels in both patients with psychosis and unaffected healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

Dendrimer-2PMPA selectively blocks upregulated microglial GCPII activity and improves cognition in a mouse model of multiple sclerosis

Hollinger¹,

Sharma²,

Tallon³

et al. 2022

Nanotheranostics

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Cognitive impairment is a common aspect of multiple sclerosis (MS) for which there are no treatments. Reduced brain N-acetylaspartylglutamate (NAAG) levels are linked to impaired cognition in various neurological diseases, including MS. NAAG levels are regulated by glutamate carboxypeptidase II (GCPII), which hydrolyzes the neuropeptide to N-acetyl-aspartate and glutamate. GCPII activity is upregulated multifold in microglia following neuroinflammation. Although several GCPII inhibitors, such as 2-PMPA, elevate brain NAAG levels and restore cognitive function in preclinical studies when given at high systemic doses or via direct brain injection, none are clinically available due to poor bioavailability and limited brain penetration. Hydroxyl-dendrimers have been successfully used to selectively deliver drugs to activated glia. Methods: We attached 2-PMPA to hydroxyl polyamidoamine (PAMAM) dendrimers (D-2PMPA) using a click chemistry approach. Cy5-labelled-D-2PMPA was used to visualize selective glial uptake in vitro and in vivo. D-2PMPA was evaluated for anti-inflammatory effects in LPS-treated glial cultures. In experimental autoimmune encephalomyelitis (EAE)-immunized mice, D-2PMPA was dosed biweekly starting at disease onset and cognition was assessed using the Barnes maze, and GCPII activity was measured in CD11b+ hippocampal cells. Results: D-2PMPA showed preferential uptake into microglia and robust anti-inflammatory activity, including elevations in NAAG, TGFβ, and mGluR3 in glial cultures. D-2PMPA significantly improved cognition in EAE mice, even though physical severity was unaffected. GCPII activity increased >20-fold in CD11b+ cells from EAE mice, which was significantly mitigated by D-2PMPA treatment. Conclusions: Hydroxyl dendrimers facilitate targeted drug delivery to activated microglia. These data support further development of D-2PMPA to attenuate elevated microglial GCPII activity and treat cognitive impairment in MS.

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“…Zink et al report on a fascinating, complex investigation of this. 5 They looked at the relationships between the expression of the genes FOLH1 (coding for GCPII, which regulates the amount of NAAG in the synapse) and GRM3 (coding for the mGluR3). They found that a missense mutation of FOLH1 was associated with decreased NAAG, and that NAAG levels in the synapse were positively correlated with cognitive performance.…”

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confidence: 99%

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Tracy¹,

Joyce²,

Albertson³

et al. 2021

Br J Psychiatry

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Association of Missense Mutation in FOLH1 With Decreased NAAG Levels and Impaired Working Memory Circuitry and Cognition

Cited by 35 publications

References 67 publications

Mice deficient in the NAAG synthetase II gene Rimkla are impaired in a novel object recognition task

Mice deficient in the NAAG synthetase II gene Rimkla are impaired in a novel object recognition task

Dendrimer-2PMPA selectively blocks upregulated microglial GCPII activity and improves cognition in a mouse model of multiple sclerosis

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