Molecular Biology and Genetics / Moleküler Biyoloji ve Genetik
Permanent URI for this collectionhttps://hdl.handle.net/11147/9
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Article Citation - Scopus: 8The Second Case of Saposin a Deficiency and Altered Autophagy(Springer Verlag, 2018) Köse, Melis; Akyıldız Demir, Seçil; Akıncı, Gülçin; Eraslan, Cenk; Yılmaz, Ünsal; Ceylaner, Serdar; Sözmen Yıldırım, Eser; Seyrantepe, VolkanKrabbe disease is a lysosomal storage disease caused by galactosylceramidase deficiency, resulting in neurodegeneration with a rapid clinical downhill course within the first months of life in the classic infantile form. This process may be triggered by the accumulation of galactosylceramide (GalCer) in nervous tissues. Both the enzyme galactosylceramidase and its in vivo activator molecule, saposin A, are essential during GalCer degradation. A clinical manifestation almost identical to Krabbe disease is observed when, instead of the galactosylceramidase protein, the saposin A molecule is defective. Saposin A results from posttranslational processing of the precursor molecule, prosaposin, encoded by the PSAP gene. Clinical and neuroimaging findings in a 7-month-old child strongly suggested Krabbe disease, but this condition was excluded by enzymatic and genetic testing. However, at whole exome sequencing, the previously undescribed homozygous, obviously pathogenic PSAP gene NM_002778.3: c.209T>G(p.Val70Gly) variant was determined in the saposin A domain of the PSAP gene. Fibroblast studies showed GalCer accumulation and the activation of autophagy for the first time in a case of human saposin A deficiency. Our patient represents the second known case in the literature and provides new information concerning the pathophysiology of saposin A deficiency and its intralysosomal effects.Article Citation - WoS: 14Citation - Scopus: 15Neuraminidase-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(Elsevier Ltd., 2015) Timur, Zehra Kevser; Akyıldız Demir, Seçil; Marsching, C.; Sandhoff, R.; Seyrantepe, VolkanTaySachs disease is a severe lysosomal storage disorder caused bymutations in the HEXA gene coding for? subunit of lysosomal β-Hexosaminidase A enzyme, which converts GM2 to GM3 ganglioside. HexA mice, depleted of the β-Hexosaminidase A iso-enzyme, remain asymptomatic up to 1 year of age because of a metabolic bypass by neuraminidase(s). These enzymes remove a sialic acid residue converting GM2 to GA2,which is further degraded by the still intact β-Hexosaminidase B iso-enzyme into lactosylceramide. A previously identified ganglioside metabolizing neuraminidase, Neu4, is abundantly expressed in the mouse brain and has activity against gangliosides like GM2 in vitro. Neu4 mice showed increased GD1a and decreased GM1 ganglioside in the brain suggesting the importance of the Neu4 in ganglioside catabolism. Mice with targeted disruption of both HexA and Neu4 genes showed accumulating GM2 ganglioside and epileptic seizures with 40% penetrance, indicating that the neuraminidase Neu4 is a modulatory gene, but may not be the only neuraminidase contributing to the metabolic bypass in HexA mice. Therefore, we elucidated the biological role of neuraminidase-1 in ganglioside degradation in mouse. Analysis of HexANeu1 and HexANeu4Neu1 mice models showed significant contribution of neuraminidase-1 on B-series ganglioside degradation in the brain. Therefore, we speculate that other neuraminidase/neuraminidases such as Neu2 and/or Neu3 might be also involved in the ganglioside degradation pathway in HexA mice.