Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides

Pan, Xuefang; Aragão, Camila De Britto Pará De; Velasco-Martín, Juan P.; Priestman, David A.; Wu, Harry Y.; Takahashi, Kyoko; Yamaguchi, Kazunori; Sturiale, Luisa; Garozzo, Domenico; Platt, Frances M.; Lamarche-Vane, Nathalie; Morales, Carlos R.; Miyagi, Taeko; Pshezhetsky, Alexey V.

doi:10.1096/fj.201601299r

Cited by 49 publications

(73 citation statements)

References 37 publications

(58 reference statements)

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“…In the mouse brain, NEU1, NEU3 and NEU4 show similar expression, each enzyme contributing to ~30% of total acidic neuraminidase activity against the synthetic substrate, 2′-(4-methylumbelliferyl)-α-D-N-acetylneuraminic acid (4MU-NeuAc). In the brain tissues of Neu1, Neu3 or Neu4 knockout (KO) mice, the activity is reduced to 70% of that in the wild-type (WT) brain, while in the brain of Neu3/Neu4 double-knockout mice, the residual activity does not exceed 30% of the WT [ 27 , 38 ]. Similar values were obtained by measuring neuraminidase activity in the presence of specific inhibitors of individual neuraminidase enzymes [ 39 ].…”

Section: Neuraminidases 1 3 and 4 Are The Main Sgc Processing Enzymementioning

confidence: 99%

Keeping it trim: roles of neuraminidases in CNS function

Pshezhetsky

Ashmarina

2018

Glycoconj J

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The sialylated glyconjugates (SGC) are found in abundance on the surface of brain cells, where they form a dense array of glycans mediating cell/cell and cell/protein recognition in numerous physiological and pathological processes. Metabolic genetic blocks in processing and catabolism of SGC result in development of severe storage disorders, dominated by CNS involvement including marked neuroinflammation and neurodegeneration, the pathophysiological mechanisms of which are still discussed. SGC patterns in the brain are cell and organelle-specific, dynamic and maintained by highly coordinated processes of their biosynthesis, trafficking, processing and catabolism. The changes in the composition of SGC during development and aging of the brain cannot be explained based solely on the regulation of the SGC-synthesizing enzymes, sialyltransferases, suggesting that neuraminidases (sialidases) hydrolysing the removal of terminal sialic acid residues also play an essential role. In the current review we summarize the roles of three mammalian neuraminidases: neuraminidase 1, neuraminidase 3 and neuraminidase 4 in processing brain SGC. Emerging data demonstrate that these enzymes with different, yet overlapping expression patterns, intracellular localization and substrate specificity play essential roles in the physiology of the CNS.

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Section: Neuraminidases 1 3 and 4 Are The Main Sgc Processing Enzymementioning

confidence: 99%

Keeping it trim: roles of neuraminidases in CNS function

Pshezhetsky

Ashmarina

2018

Glycoconj J

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“…Within the cytoplasm, CMP-Neu5Ac binds to GNE providing a negative feedback regulation of de novo Neu5Ac synthesis. Free Neu5Ac is also generated by the lysosomal salvage pathway, where sialic acids are released from sialoglycoconjugates by neuraminidases 1, 3, and 4 (5,6). Neu5Ac is then transported to the cytosol by sialin, encoded by SLC17A5, for synthesis of CMP-Neu5Ac.…”

Section: Introductionmentioning

confidence: 99%

Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function

Wen¹,

Tarailo‐Graovac²,

Brand-Arzamendi³

et al. 2018

JCI Insight

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Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.

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“…The mouse models of MPSIIIC (Hgsnat Geo ), sialidosis (Neu1 -/-) and Tay-Sachs (Hexa -/-) in C57BL/6J genetic background have been previously described (13,(26)(27)(28). The experiments were conducted for both male and female mice and the data analyzed to determine the differences between sexes.…”

Section: Animalsmentioning

confidence: 99%

Early defects in lysosomal storage diseases disrupt excitatory synaptic transmission

Aragao

Cevallos

Bose

et al. 2020

Preprint

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AbstractAt least two thirds of patients affected with lysosomal storage disorders (LSD) exhibit neurological symptoms. For mucopolysaccharidosis type IIIC (MPS IIIC, Sanfilippo disease type C) caused by mutations in the HGSNAT gene and lysosomal storage of heparan sulfate the major burden is progressive and severe neuropsychiatric problems, mental retardation, and dementia though to be mainly mediated by neurodegeneration. HGSNAT knockout mice match human clinical phenotype and develop hyperactivity followed by memory impairment and death.In order to understand whether early clinical symptoms in MPS IIIC mice occurring before the onset of massive neurodegeneration are caused by neuronal dysfunction we studied synaptic transmission and morphology in cultured hippocampal and CA1 pyramidal neurons of MPSIIIC mice. Synaptic spines were also studied in other mouse LSD models and postsynaptic densities in post-mortem cortices of human neurological MPS patients.Cultured hippocampal and CA1 pyramidal neurons of MPS IIIC mice showed a drastic decrease or abnormal distribution of multiple pre- and postsynaptic proteins that could be rescued in vitro and in vivo by virus-mediated gene correction. Dendritic spine densities were immature in cultured hippocampal MPS IIIC mouse neurons and reduced in pyramidal neurons of mouse models of MPS IIIC and other (Tay-Sachs, sialidosis) LSD starting from postnatal day 10. MPS IIIC neurons presented alterations in frequency and amplitude of miniature excitatory and inhibitory postsynaptic currents, sparse synaptic vesicles, reduced postsynaptic densities, disorganised microtubule network and partially impaired axonal transport of synaptic proteins. Postsynaptic densities were also reduced in post-mortem cotrees of human MPS I, II, IIIA, C and D patients suggesting that the pathology is common for these neurological LSD.Together, our results demonstrate that lysosomal storage causes alterations in synaptic structure and abnormalities in neurotransmission originating from disrupted vesicular transport and preceding the first cognitive symptoms and suggest drugs known to affect synaptic transmission can be potentially applied to treat behavioral and cognitive defects in neurological LSD patients.

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Neuraminidases 3 and 4 regulate neuronal function by catabolizing brain gangliosides

Cited by 49 publications

References 37 publications

Keeping it trim: roles of neuraminidases in CNS function

Keeping it trim: roles of neuraminidases in CNS function

Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function

Early defects in lysosomal storage diseases disrupt excitatory synaptic transmission

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