Insulin and serine metabolism as sex-specific hallmarks of Alzheimer’s disease in the human hippocampus

Maffioli, Elisa; Murtas, Giulia; Rabattoni, Valentina; Badone, Beatrice; Tripodi, Farida; Iannuzzi, Filomena; Licastro, Danilo; Nonnis, Simona; Rinaldi, Anna Maria; Motta, Zoraide; Sacchi, Silvia; Canu, Nadia; Tedeschi, Gioacchino; Coccetti, Paola; Pollegioni, Loredano

doi:10.1016/j.celrep.2022.111271

Cited by 30 publications

(19 citation statements)

References 91 publications

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“…The reaction in the physiological direction, leading to the production of l ‐Ser, was investigated using the three enzymes of the PP, 3PG, NAD + and l ‐Glu, following NADH production at 340 nm in a continuous assay at pH 7 and 37 °C. The concentration of the three enzymes in the human hippocampus [22] and differentiated astrocytes (Tripodi F., Motta Z., Murtas G., Rabattoni V., Nonnis S., Grassi Scalvini F., Rinaldi A.M., Rizzi R, Bearzi C., Badone B., Sacchi S., Tedeschi G., Maffioli E., Coccetti P., Pollegioni L, unpublished data) was recently determined, as well as the concentration of the main metabolites related to the PP (Table 3). In order to simulate the physiological conditions, the reactions were performed using the concentration of the PP enzymes as determined in differentiated astrocytes, i.e.…”

Section: Resultsmentioning

confidence: 99%

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The human phosphorylated pathway: a multienzyme metabolic assembly for l‐serine biosynthesis

et al. 2023

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De novo L-serine biosynthesis in the mammalian astrocytes proceeds via a linear, three-step pathway (the phosphorylated pathway) catalysed by 3phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP). The first reaction, catalysed by PHGDH and using the glycolytic intermediate 3phosphoglycerate, is strongly shifted towards the reagents, and coupling to the following step by PSAT is required to push the equilibrium towards Lserine formation; the last step, catalysed by PSP, is virtually irreversible and inhibited by the final product L-serine. Very little is known about the regulation of the human phosphorylated pathway and the ability of the three enzymes to organise in a complex with potential regulatory functions. Here, the complex formation was investigated in differentiated human astrocytes, by proximity ligation assay, and in vitro on the human recombinant enzymes. The results indicate that the three enzymes co-localise in cytoplasmic clusters that more stably engage PSAT and PSP. Although in vitro analyses based on native PAGE, size exclusion chromatography and cross-linking experiments do not show the formation of a stable complex, kinetic studies of the reconstituted pathway using physiological enzyme and substrate concentrations support cluster formation and indicate that PHGDH catalyses the rate-limiting step while PSP reaction is the driving force for the whole pathway. The enzyme agglomerate assembly of the phosphorylated pathway (the putative 'serinosome') delivers a relevant level of sophistication to the control of L-serine biosynthesis in human cells, a process strictly related to the modulation of the brain levels of Dserine and glycine, the main co-agonists of N-methyl-D-aspartate receptors and various pathological states.

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Section: Resultsmentioning

confidence: 99%

“…The PP is also linked to cancer, since the hyperactivation of the l ‐Ser/glycine biosynthetic pathway drives oncogenesis; for a review, see [21]. Furthermore, the PP was recently linked to mechanisms differing between genders in healthy ageing and Alzheimer's disease onset [22].…”

Section: Introductionmentioning

confidence: 99%

The human phosphorylated pathway: a multienzyme metabolic assembly for l‐serine biosynthesis

et al. 2023

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“…D-AAs have been involved in pathological processes, including neurological diseases (e.g., psychosis, Alzheimer’s disease, and amyotrophic lateral sclerosis), psychiatric disorders (e.g., schizophrenia and bipolar disorder), chronic kidney disease, and cancer [ 38 , 39 , 40 , 41 ]. The levels of relevant D-AAs have been reported to be significantly altered in some pathological conditions compared to healthy controls [ 40 , 41 , 42 , 43 , 44 , 45 ] and, thus, might represent useful biomarkers (see [ 46 ]). The potential of D-AAs as therapeutic agents for treating neurological diseases and tissue/organ injury, ameliorating reproduction function, and preventing biofilm infection, has recently been reviewed [ 47 ].…”

Section: Introductionmentioning

confidence: 99%

D-Amino Acids and Cancer: Friends or Foes?

Murtas

Pollegioni

2023

IJMS

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α-amino acids exist in two configurations, named D-(dextro) and L-(levo) enantiomers. L-amino acids are used in protein synthesis and play a central role in cell metabolism. The effects of the L-amino acid composition of foods and the dietary modifications of this composition on the efficacy of cancer therapies have been widely investigated in relation to the growth and reproduction of cancerous cells. However, less is known about the involvement of D-amino acids. In recent decades, D-amino acids have been identified as natural biomolecules that play interesting and specific roles as common components of the human diet. Here, we focus on recent investigations showing altered D-amino acid levels in specific cancer types and on the various roles proposed for these biomolecules related to cancer cell proliferation, cell protection during therapy, and as putative, innovative biomarkers. Notwithstanding recent progress, the relationship between the presence of D-amino acids, their nutritional value, and cancer cell proliferation and survival represents an underrated scientific issue. Few studies on human samples have been reported to date, suggesting a need for routine analysis of D-amino acid content and an evaluation of the enzymes involved in regulating their levels in clinical samples in the near future.

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“…For example, neurological disorders, such as Alzheimer's and Parkinson's disease, have been linked to the presence of D-serine (D-Ser) in the mammalian brain. 3,4 D-amino acids can also act as endogenous neurotransmitters that improve learning and memory in rats, 5,6 and chiral amino acids are emerging as new disease biomarkers. Therefore, an efficient and sensitive method that disassembles chiral amino molecules and analyzes them qualitatively and quantitatively is essential for diagnosing diseases.…”

Section: Introductionmentioning

confidence: 99%

Development and evaluation of a novel fluorescent chiral derivatization reagent DBD-S-M-Pro: first observation of four chiral amino acids in human hair

et al. 2023

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Insulin and serine metabolism as sex-specific hallmarks of Alzheimer’s disease in the human hippocampus

Cited by 30 publications

References 91 publications

The human phosphorylated pathway: a multienzyme metabolic assembly for l‐serine biosynthesis

The human phosphorylated pathway: a multienzyme metabolic assembly for l‐serine biosynthesis

D-Amino Acids and Cancer: Friends or Foes?

Development and evaluation of a novel fluorescent chiral derivatization reagent DBD-S-M-Pro: first observation of four chiral amino acids in human hair

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