Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model

Haslinger, Denise; Waltes, Regina; Yousaf, Afsheen; Lindlar, Silvia; Schneider, Ines; Lim, Chai K.; Tsai, Meng Miao; Garvalov, Boyan K.; Acker‐Palmer, Amparo; Krezdorn, Nicolas; Rotter, Björn; Acker, Till; Guillemin, Gilles J.; Fulda, Simone; Freitag, Christine M.; Chiocchetti, Andreas G.

doi:10.1186/s13229-018-0239-z

Cited by 34 publications

(38 citation statements)

References 76 publications

(93 reference statements)

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“…In this context, it should be noticed that quinolinate phosphoribosyltransferase (QPRT), which belongs to the phosphoribosyltransferase family and is involved in de novo NAD biosynthesis using quinolinic acid (QA) as a precursor in both prokaryotes and eukaryotes, has not been thoroughly investigated in the context of cancer and inflammation, but there are evidences that also this enzyme might play a role (Hinsch et al, 2009;Sahm et al, 2013;Ullmark et al, 2017;Haslinger et al, 2018).…”

Section: Naprt Is An Important Counterpart To Nampt In Nad Metabolismmentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

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Nicotinamide adenine dinucleotide (NAD) is a cofactor of many enzymatic reactions as well as being a substrate for a number of NAD-consuming enzymes (e.g., PARPS, sirtuins, etc). NAD can be synthesized de novo starting from tryptophan, nicotinamide, nicotinic acid, or nicotinamide riboside from the diet. On the other hand, the nicotinamide that is liberated by NAD-consuming enzymes can be salvaged to reform NAD. In this former instance, nicotinamide phosphoribosyltransferase (NAMPT) is the bottleneck enzyme. In the many cells in which the salvage pathway is predominant, NAMPT, therefore, represents an important controller of intracellular NAD concentrations, and as a consequence of energy metabolism. It is, therefore, not surprising that NAMPT is over expressed by tumoral cells, which take advantage from this to sustain growth rate and tumor progression. This has led to the initiation of numerous medicinal chemistry programs to develop NAMPT inhibitors in the context of oncology. More recently, however, it has been shown that NAMPT inhibitors do not solely target the tumor but also have an effect on the immune system. To add complexity, this enzyme can also be secreted by cells, and in the extracellular space it acts as a cytokine mainly through the activation of Toll like Receptor 4 (TLR4), although it has not been clarified yet if this is the only receptor responsible for its actions. While specific small molecules have been developed only against the intracellular form of NAMPT, growing evidences sustain the possibility to target the extracellular form. In this contribution, the most recent evidences on the medicinal chemistry of NAMPT will be reviewed, together with the key elements that sustain the hypothesis of NAMPT targeting and the drawbacks so far encountered.

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Section: Naprt Is An Important Counterpart To Nampt In Nad Metabolismmentioning

confidence: 99%

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

et al. 2020

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“…Such abnormalities could affect tryptophan availability during brain development, indirectly altering serotonin and KP activity. Furthermore, the tryptophan metabolism-related enzyme quinolinate phosphoribosyl-transferase (QPRT) affects the regulation of genes and gene networks previously implicated in ASDs [ 154 ] and, at the same time, a deletion in 16p11.2, the chromosomal regions responsible for QPRT codification, has strongly been associated to ASD [ 154 ].…”

Section: The Kynurenines Pathwaymentioning

confidence: 99%

Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway

et al. 2020

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Autism Spectrum Disorder (ASD) etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and the Kynurenine pathway; here we review the nature of these interactions. Pre-natal or neonatal infections would induce microglial activation, with secondary consequences on behavior, cognition and neurotransmitter networks. Peripherally, higher levels of pro-inflammatory cytokines and anti-brain antibodies have been identified. Increased frequency of autoimmune diseases, allergies, and recurring infections have been demonstrated both in autistic patients and in their relatives. Genetic studies have also identified some important polymorphisms in chromosome loci related to the human leukocyte antigen (HLA) system. The persistence of immune-inflammatory deregulation would lead to mitochondrial dysfunction and oxidative stress, creating a self-sustaining cytotoxic loop. Chronic inflammation activates the Kynurenine pathway with an increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in the glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of the Kynurenine branch induces depletion of melatonin and serotonin, worsening ASD symptoms. Thus, in genetically predisposed subjects, aberrant neurodevelopment may derive from a complex interplay between inflammatory processes, mitochondrial dysfunction, oxidative stress and Kynurenine pathway overexpression. To validate this hypothesis a new translational research approach is necessary.

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“…In the de novo pathway, tryptophan is first converted to quinolinic acid (QA) through a series of steps; QA is converted to nicotinic acid mononucleotide (NAMN) via quinolinate phosphoribosyltransferase (QPRT) and is then converted to NAD + via nicotinamide nucleotide adenylyltransferase (NMNAT) and NAD synthetase (NADS). In normal cells, QPRT expression follows a tissue-specific distribution; more recent insights have revealed that QPRT expression is altered in some cancer cells (4)(5)(6)(7). The Preiss-Handler pathway converts nicotinic acid (NA) to NAMN through nicotinate phosphoribosyltransferase (NAPRT), an enzyme that is widely expressed in normal tissues but variably expressed in cancer cells (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

Heske

2020

Front. Oncol.

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Tumor cells have increased requirements for NAD +. Thus, many cancers exhibit an increased reliance on NAD + production pathways. This dependence may be exploited therapeutically through pharmacological targeting of NAMPT, the rate-limiting enzyme in the NAD + salvage pathway. Despite promising preclinical data using NAMPT inhibitors in cancer models, early NAMPT inhibitors showed limited efficacy in several early phase clinical trials, necessitating the identification of strategies, such as drug combinations, to enhance their efficacy. While the effect of NAMPT inhibitors on impairment of energy metabolism in cancer cells has been well-described, more recent insights have uncovered a number of additional targetable cellular processes that are impacted by inhibition of NAMPT. These include sirtuin function, DNA repair machinery, redox homeostasis, molecular signaling, cellular stemness, and immune processes. This review highlights the recent findings describing the effects of NAMPT inhibitors on the non-metabolic functions of malignant cells, with a focus on how this information can be leveraged clinically. Combining NAMPT inhibitors with other therapies that target NAD +-dependent processes or selecting tumors with specific vulnerabilities that can be co-targeted with NAMPT inhibitors may represent opportunities to exploit the multiple functions of this enzyme for greater therapeutic benefit.

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Loss of the Chr16p11.2 ASD candidate gene QPRT leads to aberrant neuronal differentiation in the SH-SY5Y neuronal cell model

Cited by 34 publications

References 76 publications

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Recent Advances in NAMPT Inhibitors: A Novel Immunotherapic Strategy

Analyzing the Potential Biological Determinants of Autism Spectrum Disorder: From Neuroinflammation to the Kynurenine Pathway

Beyond Energy Metabolism: Exploiting the Additional Roles of NAMPT for Cancer Therapy

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