Combined replacement effects of human modified β-hexosaminidase B and GM2 activator protein on GM2 gangliosidoses fibroblasts

GM2 gangliosidoses are autosomal recessive lysosomal storage diseases (LSDs) caused by mutations in the HEXA, HEXB and GM2A genes, which encode the human lysosomal β-hexosaminidase (Hex) α- and β-subunits, and GM2 activator protein (GM2A), respectively. These diseases are associated with excessive accumulation of GM2 ganglioside (GM2) in the brains of patients with neurological symptoms. Here we established a CHO cell line overexpressing human GM2A, and purified GM2A from the conditioned medium, which was taken up by fibroblasts derived from a patient with GM2A deficiency, and had the therapeutic effects of reducing the GM2 accumulated in fibroblasts when added to the culture medium. We also demonstrated for the first time that recombinant GM2A could enhance the replacement effect of human modified HexB (modB) with GM2-degrading activity, which is composed of homodimeric altered β-subunits containing a partial amino acid sequence of the α-subunit, including the GSEP loop necessary for binding to GM2A, on reduction of the GM2 accumulated in fibroblasts derived from a patient with Tay-Sachs disease, a HexA (αβ heterodimer) deficiency, caused by HEXA mutations. We predicted the same manner of binding of GM2A to the GSEP loop located in the modified HexB β-subunit to that in the native HexA α-subunit on the basis of the x-ray crystal structures. These findings suggest the effectiveness of combinational replacement therapy involving the human modified HexB and GM2A for GM2 gangliosidoses

Combined replacement effects of human modified β-hexosaminidase B and GM2 activator protein on GM2 gangliosidoses fibroblasts

AbstractGM2 gangliosidoses are autosomal recessive lysosomal storage diseases (LSDs) caused by mutations in the HEXA, HEXB and GM2A genes, which encode the human lysosomal β-hexosaminidase (Hex) α- and β-subunits, and GM2 activator protein (GM2A), respectively. These diseases are associated with excessive accumulation of GM2 ganglioside (GM2) in the brains of patients with neurological symptoms. Here we established a CHO cell line overexpressing human GM2A, and purified GM2A from the conditioned medium, which was taken up by fibroblasts derived from a patient with GM2A deficiency, and had the therapeutic effects of reducing the GM2 accumulated in fibroblasts when added to the culture medium. We also demonstrated for the first time that recombinant GM2A could enhance the replacement effect of human modified HexB (modB) with GM2-degrading activity, which is composed of homodimeric altered β-subunits containing a partial amino acid sequence of the α-subunit, including the GSEP loop necessary for binding to GM2A, on reduction of the GM2 accumulated in fibroblasts derived from a patient with Tay-Sachs disease, a HexA (αβ heterodimer) deficiency, caused by HEXA mutations. We predicted the same manner of binding of GM2A to the GSEP loop located in the modified HexB β-subunit to that in the native HexA α-subunit on the basis of the x-ray crystal structures. These findings suggest the effectiveness of combinational replacement therapy involving the human modified HexB and GM2A for GM2 gangliosidoses

Non-strange dibaryons studied in coherent double neutral-meson photoproduction on the deuteron

The B = 2 bound/resonance state (dibaryon) is an interesting object, which can be a molecule consisting of two baryons or a spatially compact hexaquark hadron object. The yd ^ n°n°d reaction has been experimentally investigated at incident energies ranging from 0.58 to 1.15 GeV to study non-strange dibaryons. The angular distributions of deuteron emission in the yd center-of-mass energy cannot be reproduced by quasi-free production of two neutral pions followed by deuteron coalescence. Additionally a 2.14-GeV peak is observed in the n°d invariant mass distribution. These suggest a sequential process such as yd ^ RIS ^ n°RIV ^ n°n°d with an isoscalar dibaryon RIS and an isovector dibaryon RIV. Since the mass of the observed isoscalar dibaryons are close to the sum of the nucleon (N) and nucleon resonance (N*) masses, an S-wave NN* molecule may play a role as a doorway to a dibaryon

Non-strange dibaryons studied in coherent double neutral-meson photoproduction on the deuteron

The B = 2 bound/resonance state (dibaryon) is an interesting object, which can be a molecule consisting of two baryons or a spatially compact hexaquark hadron object. The yd ^ n°n°d reaction has been experimentally investigated at incident energies ranging from 0.58 to 1.15 GeV to study non-strange dibaryons. The angular distributions of deuteron emission in the yd center-of-mass energy cannot be reproduced by quasi-free production of two neutral pions followed by deuteron coalescence. Additionally a 2.14-GeV peak is observed in the n°d invariant mass distribution. These suggest a sequential process such as yd ^ RIS ^ n°RIV ^ n°n°d with an isoscalar dibaryon RIS and an isovector dibaryon RIV. Since the mass of the observed isoscalar dibaryons are close to the sum of the nucleon (N) and nucleon resonance (N*) masses, an S-wave NN* molecule may play a role as a doorway to a dibaryon

Photoproduction of η-mesons off C and Cu Nuclei for Photon Energies below 1.1 GeV(I. Nuclear Physics)

The η-meson photoproduction cross sections have been measured on C and Cu targets for photon energies between 600 and 1100MeV to investigate the behavior of the S_11 (1535) resonance in a nucleus. The excitation functions of the cross section as well as angular and momentum distributions of η-mesons are in quantitative agreement with Quantum Molecular Dynamics (QMD) model calculations, in which the η-meson emission processes other than the S_11 (1535) resonance are also incorporated as proposed in the η-MAID model. It is shown that the excitation of the D_15 (1675) resonance might play an important role for E_γ>900MeV

J-PARC hadron experimental facility extension project

The J-PARC Hadron Experimental Facility was constructed with an aim to explore the origin and evolution of matter in the universe through experiments with intense particle beams. In the past decade, many results from particle and nuclear physics experiments have been obtained at the present facility. To expand the physics programs to as yet unexplored regions, the extension project of the Hadron Experimental Facility has been extensively discussed. This contribution presents the physics of the extension of the Hadron Experimental Facility to resolve issues related to strangeness nuclear physics, hadron physics, and flavor physics