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Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease.

Valles-Ortega J, Duran J, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Cañas X, Soriano E, Delgado-García JM, Gruart A, Guinovart JJ - EMBO Mol Med (2011)

Bottom Line: They also had LBs in the soma and some processes of PV(+) interneurons.This phenomenon was accompanied by the progressive loss of these neuronal cells and, importantly, neurophysiological alterations potentially related to impairment of hippocampal function.Our results emphasize the relevance of the laforin-malin complex in the control of glycogen metabolism and highlight altered glycogen accumulation as a key contributor to neurodegeneration in LD.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Spain.

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Localization of LBs in hippocampal astroglia, microglia and neuronsRepresentative images from 4-month-old (A) and 11-month-old (A–C) malin KO hippocampus.Orthogonal confocal sections are shown for astrocytes containing polyglucosan accumulation in the hippocampus of 4- and 11-month-old KO mice. Antibodies were used against GFAP (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Scale bar = 10 µm.Confocal images are shown for DG and CA1 hippocampal regions. Antibodies were used against parvalbumin (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Polyglucosan accumulation can be observed within the somas (white arrows) and some processes (white arrowheads) of PV+ interneurons. Scale bar = 10 µm. 3X = 3-fold magnification.Electron microscopy images are shown for CA1. Micrographs depict the presence of LBs and glycogen granules in dendrites (a1, a2, b1, b2). LBs were also found in astrocytes (c1, c2). Microglial cells with some engulfed LBs were observed (d). *, Lafora Body; +, glycogen granule; black arrowhead: postsynaptic density; B: synaptic bouton; DS: dendritic spine. a2, b2 and c2 are magnifications of the boxes in a1, b1 and c1. Scale bars are 5 µm in c1 and 0.5 µm in a1, a2, b1, b2, c2 and d.
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fig06: Localization of LBs in hippocampal astroglia, microglia and neuronsRepresentative images from 4-month-old (A) and 11-month-old (A–C) malin KO hippocampus.Orthogonal confocal sections are shown for astrocytes containing polyglucosan accumulation in the hippocampus of 4- and 11-month-old KO mice. Antibodies were used against GFAP (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Scale bar = 10 µm.Confocal images are shown for DG and CA1 hippocampal regions. Antibodies were used against parvalbumin (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Polyglucosan accumulation can be observed within the somas (white arrows) and some processes (white arrowheads) of PV+ interneurons. Scale bar = 10 µm. 3X = 3-fold magnification.Electron microscopy images are shown for CA1. Micrographs depict the presence of LBs and glycogen granules in dendrites (a1, a2, b1, b2). LBs were also found in astrocytes (c1, c2). Microglial cells with some engulfed LBs were observed (d). *, Lafora Body; +, glycogen granule; black arrowhead: postsynaptic density; B: synaptic bouton; DS: dendritic spine. a2, b2 and c2 are magnifications of the boxes in a1, b1 and c1. Scale bars are 5 µm in c1 and 0.5 µm in a1, a2, b1, b2, c2 and d.

Mentions: While 4-month-old KO brains showed mainly astrocyte-associated LB accumulation (Figs 5 and 6A), 11-month-old counterparts showed LBs in astrocytes (Figs 5 and 6A) and in the cell bodies of neurons (Fig 5). Neuronal LBs were very conspicuous in the neuronal somata of hippocampal PV+ interneurons and were occasionally found in their dendritic processes (Fig 6B).


Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease.

Valles-Ortega J, Duran J, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Cañas X, Soriano E, Delgado-García JM, Gruart A, Guinovart JJ - EMBO Mol Med (2011)

Localization of LBs in hippocampal astroglia, microglia and neuronsRepresentative images from 4-month-old (A) and 11-month-old (A–C) malin KO hippocampus.Orthogonal confocal sections are shown for astrocytes containing polyglucosan accumulation in the hippocampus of 4- and 11-month-old KO mice. Antibodies were used against GFAP (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Scale bar = 10 µm.Confocal images are shown for DG and CA1 hippocampal regions. Antibodies were used against parvalbumin (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Polyglucosan accumulation can be observed within the somas (white arrows) and some processes (white arrowheads) of PV+ interneurons. Scale bar = 10 µm. 3X = 3-fold magnification.Electron microscopy images are shown for CA1. Micrographs depict the presence of LBs and glycogen granules in dendrites (a1, a2, b1, b2). LBs were also found in astrocytes (c1, c2). Microglial cells with some engulfed LBs were observed (d). *, Lafora Body; +, glycogen granule; black arrowhead: postsynaptic density; B: synaptic bouton; DS: dendritic spine. a2, b2 and c2 are magnifications of the boxes in a1, b1 and c1. Scale bars are 5 µm in c1 and 0.5 µm in a1, a2, b1, b2, c2 and d.
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fig06: Localization of LBs in hippocampal astroglia, microglia and neuronsRepresentative images from 4-month-old (A) and 11-month-old (A–C) malin KO hippocampus.Orthogonal confocal sections are shown for astrocytes containing polyglucosan accumulation in the hippocampus of 4- and 11-month-old KO mice. Antibodies were used against GFAP (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Scale bar = 10 µm.Confocal images are shown for DG and CA1 hippocampal regions. Antibodies were used against parvalbumin (green) and polyglucosan (red). Hoechst (blue) was used for nuclear staining. Polyglucosan accumulation can be observed within the somas (white arrows) and some processes (white arrowheads) of PV+ interneurons. Scale bar = 10 µm. 3X = 3-fold magnification.Electron microscopy images are shown for CA1. Micrographs depict the presence of LBs and glycogen granules in dendrites (a1, a2, b1, b2). LBs were also found in astrocytes (c1, c2). Microglial cells with some engulfed LBs were observed (d). *, Lafora Body; +, glycogen granule; black arrowhead: postsynaptic density; B: synaptic bouton; DS: dendritic spine. a2, b2 and c2 are magnifications of the boxes in a1, b1 and c1. Scale bars are 5 µm in c1 and 0.5 µm in a1, a2, b1, b2, c2 and d.
Mentions: While 4-month-old KO brains showed mainly astrocyte-associated LB accumulation (Figs 5 and 6A), 11-month-old counterparts showed LBs in astrocytes (Figs 5 and 6A) and in the cell bodies of neurons (Fig 5). Neuronal LBs were very conspicuous in the neuronal somata of hippocampal PV+ interneurons and were occasionally found in their dendritic processes (Fig 6B).

Bottom Line: They also had LBs in the soma and some processes of PV(+) interneurons.This phenomenon was accompanied by the progressive loss of these neuronal cells and, importantly, neurophysiological alterations potentially related to impairment of hippocampal function.Our results emphasize the relevance of the laforin-malin complex in the control of glycogen metabolism and highlight altered glycogen accumulation as a key contributor to neurodegeneration in LD.

View Article: PubMed Central - PubMed

Affiliation: Institute for Research in Biomedicine (IRB Barcelona) Barcelona, Spain.

Show MeSH
Related in: MedlinePlus