Neuraminidase-1 contributes significantly to the degradation of neuronal B-series gangliosides but not to the bypass of the catabolic block in Tay–Sachs mouse models

Timur, Zehra Kevser; Demir, Secil Akyildiz; Marsching, Christian; Sandhoff, Roger; Seyrantepe, Volkan

doi:10.1016/j.ymgmr.2015.07.004

Cited by 14 publications

(11 citation statements)

References 31 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further studies, however, demonstrated that NEU1 has negligible activity against ganglioside substrates, in contrast with NEU3 and NEU4 [ 29 ]. In agreement with this, Hexa −/- CathA S190A-neo mice with secondary 90% deficiency of NEU1 in the tissues do not show an increase in brain GM2 levels as compared with Hexa −/− mice [ 78 ]. Li 2001 et al .…”

Section: Catabolism Of Brain Gangliosides: Neu1 Neu3 or Neu4?supporting

confidence: 59%

Keeping it trim: roles of neuraminidases in CNS function

Pshezhetsky

Ashmarina

2018

Glycoconj J

View full text Add to dashboard Cite

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.

show abstract

Section: Catabolism Of Brain Gangliosides: Neu1 Neu3 or Neu4?supporting

confidence: 59%

Keeping it trim: roles of neuraminidases in CNS function

Pshezhetsky

Ashmarina

2018

Glycoconj J

View full text Add to dashboard Cite

show abstract

“…Interestingly, the increased presence of asialo-G M1 (G A1 ) is compatible with an alternative degradation pathway for G M1 and G A1 . The presence of a higher amount of G A1 indicates that murine enzymes exhibit a different affinity towards degradation products, which is also described in another model for G M1 -gangliosidosis [22] and for murine neuraminidases in a model for Morbus Tay-Sachs [44].…”

Section: Discussionsupporting

confidence: 57%

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Eikelberg¹,

Lehmbecker²,

Brogden³

et al. 2020

JCM

View full text Add to dashboard Cite

GM1-gangliosidosis is caused by a reduced activity of β-galactosidase (Glb1), resulting in intralysosomal accumulations of GM1. The aim of this study was to reveal the pathogenic mechanisms of GM1-gangliosidosis in a new Glb1 knockout mouse model. Glb1−/− mice were analyzed clinically, histologically, immunohistochemically, electrophysiologically and biochemically. Morphological lesions in the central nervous system were already observed in two-month-old mice, whereas functional deficits, including ataxia and tremor, did not start before 3.5-months of age. This was most likely due to a reduced membrane resistance as a compensatory mechanism. Swollen neurons exhibited intralysosomal storage of lipids extending into axons and amyloid precursor protein positive spheroids. Additionally, axons showed a higher kinesin and lower dynein immunoreactivity compared to wildtype controls. Glb1−/− mice also demonstrated loss of phosphorylated neurofilament positive axons and a mild increase in non-phosphorylated neurofilament positive axons. Moreover, marked astrogliosis and microgliosis were found, but no demyelination. In addition to the main storage material GM1, GA1, sphingomyelin, phosphatidylcholine and phosphatidylserine were elevated in the brain. In summary, the current Glb1−/− mice exhibit a so far undescribed axonopathy and a reduced membrane resistance to compensate the functional effects of structural changes. They can be used for detailed examinations of axon–glial interactions and therapy trials of lysosomal storage diseases.

show abstract

“…Surfaces of mammalian neurons are enriched in GGs of the a-and b-ganglio-series (e.g., GM1a, GD1a, GD1b, GT1a, GT1b, and polysialo-GGs), carrying up to six sialic acid residues [9]. Desialylation of complex polysialo-GGs to eventually generate GG GM1 is catabolized mainly by three membrane-bound sialidases with overlapping substrate specificities and differing subcellular location, neuraminidase NEU1, NEU3, and NEU4 [42][43][44]. The plasma membrane-bound NEU3 is the key enzyme for degradation of polysialo-GGs and is involved in many surface phenomena, whereas NEU1 is the major sialidase of endosomes and lysosomes to hydrolyze polysialo-GGs to generate GM1 [45].…”

Section: Lysosomal Catabolism Of Ggsmentioning

confidence: 99%

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Breiden

Sandhoff

2020

IJMS

View full text Add to dashboard Cite

Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann-Pick disease type A and B, and of GM2 and glucosylceramide in Niemann-Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

show abstract

Neuraminidase-1 contributes significantly to the degradation of neuronal B-series gangliosides but not to the bypass of the catabolic block in Tay–Sachs mouse models

Cited by 14 publications

References 31 publications

Keeping it trim: roles of neuraminidases in CNS function

Keeping it trim: roles of neuraminidases in CNS function

Axonopathy and Reduction of Membrane Resistance: Key Features in a New Murine Model of Human GM1-Gangliosidosis

Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

Contact Info

Product

Resources

About