Advertisement

Sites and temporal changes of gangliosides GM1/GM2 storage in the Niemann–Pick disease type C mouse brain

      Abstract

      Niemann–Pick disease type C (NPC) is a progressive neurodegenerative disorder with characteristic storage of glycolipids in the brain. This study investigated cellular origin and temporal changes of monosialoganglioside storage in the Balb/c npcnih mouse brain by immunohistochemistry. Anti-GM1 gave positive staining of the hippocampus, thalamus, cerebellar molecular and Purkinje cell layers in the 3-week old NPC mouse brain and in general, the staining progressively diminished in an age-dependent manner. Anti-GM2 gave positive staining of the hippocampus, thalamus, cerebellar granule cell layer and brainstem nuclei in the 3-week old NPC mouse brain. In contrast to GM1, GM2 staining in these regions, except for the hippocampus, progressively augmented in an age-dependent manner. Double labeling experiments with antibodies against glial fibrillary acidic protein and lysozyme showed localization of GM1 and GM2 in reactive astrocytes and macrophages, respectively. Thus in the NPC mouse brain, GM1 accumulated primarily in neurons and astrocytes whereas GM2 accumulated primarily in neurons and macrophages. Temporal profiles of storage were different from each other and depended on the cell type, presumably reflecting both developmental changes and progression of the disease process. We also investigated subcellular sites of storage in primary-cultured Purkinje cells from the neonatal NPC mouse by immunocytochemistry. In NPC Purkinje cells, GM1 accumulated both in the cytoplasm and dendrites whereas GM2 showed punctuate accumulation in perinuclear vesicles. Thus, subcellular sites of storage were also different between GM1 and GM2 in NPC neurons.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Brain and Development
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Ory D.S.
        Niemann–Pick type C: a disorder of cellular cholesterol trafficking.
        Biochim Biophys Acta. 2000; 1529: 331-339
        • Carstea E.D.
        • Morris J.A.
        • Coleman K.G.
        • Loftus S.K.
        • Zhang D.
        • Cummings C.
        • et al.
        Niemann–Pick C1 disease gene: homology to mediators of cholesterol homeostasis.
        Science. 1997; 227: 228-231
        • Davies J.P.
        • Chen F.W.
        • Ioannou Y.A.
        Transmenbrane molecular pump activity of Niemann–Pick C1 protein.
        Science. 2000; 290: 2295-2298
        • Loftus S.K.
        • Morris J.A.
        • Carstea E.D.
        • Gu J.Z.
        • Cummings C.
        • Brown A.
        • et al.
        Murine model of Niemann–Pick C disease: mutation in a cholesterol homeostasis gene.
        Science. 1997; 277: 232-235
        • Vanier M.T.
        Lipid changes in Niemann–Pick disease type C brain: personal experience and review of the literature.
        Neurochem Res. 1999; 24: 481-489
        • Elleder M.
        Niemann–Pick disease.
        Pathol Res Pract. 1989; 185: 293-328
        • Watanabe Y.
        • Akaboshi S.
        • Ishida G.
        • Takeshima T.
        • Yano T.
        • Taniguchi M.
        • et al.
        Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile Niemann–Pick disease type C.
        Brain Dev. 1998; 20: 95-97
        • Mutoh T.
        • Tokuda A.
        • Miyadai T.
        • Hamaguchi M.
        • Fujiki N.
        Ganglioside GM1 binds to the Trk protein and regulates receptor function.
        Proc Natl Acad Sci USA. 1995; 92: 5087-5091
        • Walkley S.U.
        Pyramidal neurons with ectopic dendrites in storage diseases exhibit increased GM2 ganglioside immunoreactivity.
        Neuroscience. 1995; 68: 1027-1035
        • Walkley S.U.
        • Siegal D.A.
        • Dobrenis K.
        GM2 ganglioside and pyramidal neuron dendritogenesis.
        Neurochem Res. 1995; 20: 1287-1299
        • Higashi Y.
        • Murayama S.
        • Pentchev P.G.
        • Suzuki K.
        Cerebellar degeneration in the Niemann–Pick type C mouse.
        Acta Neuropathol. 1993; 85: 175-184
        • Vanier M.T.
        • Suzuki K.
        Recent advances in elucidating Niemann–Pick C disease.
        Brain Pathol. 1998; 8: 163-174
        • Kawashima I.
        • Nagata I.
        • Tai T.
        Immunocytochemical analysis of gangliosides in rat primary cerebellar cultures using specific monoclonal antibodies.
        Brain Res. 1996; 732: 75-86
        • Molander M.
        • Berthold C.H.
        • Persson H.
        • Fredman P.
        Immunostaining of ganglioside GD1b, GD3 and GM1 in rat cerebellum: cellular layer and cell type specific associations.
        J Neurosci Res. 2000; 60: 531-542
        • Furuya S.
        • Makino A.
        • Hirabayashi Y.
        An improved method for culturing cerebellar Purkinje cells with differentiated dendrites under a mixed monolayer setting.
        Brain Res Brain Res Protoc. 1998; 3: 192-198
        • Xie C.
        • Burns D.K.
        • Turley S.D.
        • Dietschy J.M.
        Cholesterol is sequestered in the brains of mice with Niemann–Pick type C disease but turnover is increased.
        J Neuropathol Exp Neurol. 2000; 59: 1106-1117
        • Liu Y.
        • Wu Y.P.
        • Wada R.
        • Neufeld E.B.
        • Mullin K.A.
        • Howard A.C.
        • et al.
        Alleviation of neuronal ganglioside storage does not improve the clinical course of the Niemann–Pick C disease mouse.
        Hum Mol Genet. 2000; 9: 1087-1092
        • Henderson L.P.
        • Lin L.
        • Prasad A.
        • Paul C.A.
        • Chang T.Y.
        • Maue R.A.
        Embryonic striatal neurons from Niemann–Pick type C mice exhibit defects in cholesterol metabolism and neurotrophin responsiveness.
        J Biol Chem. 2000; 275: 20179-20187
        • Siegel D.A.
        • Walkley S.U.
        Growth of ectopic dendrites on cortical pyramidal neurons in neuronal storage diseases correlates with abnormal accumulation of GM2 ganglioside.
        J Neurochem. 1994; 62: 1852-1862
        • Zervas M.
        • Dobrenis K.
        • Walkley S.U.
        Neurons in Niemann–Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations.
        J Neuropathol Exp Neurol. 2001; 60: 49-64