Research ReportAltered glycosylation of α-dystroglycan in neurons of Fukuyama congenital muscular dystrophy brains
Introduction
Fukuyama congenital muscular dystrophy (FCMD) is caused by mutations in the fukutin gene (Kobayashi et al., 1998), the product of which is involved in the glycosylation of α-dystroglycan (α-DG) (Aravind and Koonin, 1999, Michele et al., 2002), a central component of the dystrophin–glycoprotein complex (Ervasti and Campbell, 1993, Henry and Campbell, 1999, Ibraghimov-Beskrovnaya et al., 1992). Hypoglycosylation of α-DG results in the decreased binding of laminin at the sarcolemma and in the subsequent dystrophic pathology of skeletal muscles (Michele et al., 2002).
As for the central nervous system, FCMD brains are characterized by cerebral and cerebellar micropolygyria (Kamoshita et al., 1976). Based on the breached glia-limitans and the protrusion of glial–neuronal tissue into the subarachnoid space, a fragile glia-limitans has been hypothesized to be a cardinal feature of the pathological process in FCMD brains (Nakano et al., 1996, Takada et al., 1987). The presence of α-DG in the glia-limitans, and in the glial endfeet of vessel walls (Michele et al., 2002, Zaccaria et al., 2001), supports the hypothesis that hypoglycosylation of α-DG results in decreased binding of glial α-DG with extracellular matrix proteins. Decreased integrity of the glia-limitans may be responsible for the protrusion of brain parenchyma and overmigration of neurons beyond the pial surface during cerebral corticogenesis. However, in contrast to the findings in muscle tissue, hypoglycosylation of α-DG has not been identified in the glia-limitans of FCMD brains. In addition, fukutin protein has been localized in both neurons and glial cells (Ohtsuka-Tsurumi et al., 2004, Saito et al., 2000, Sasaki et al., 2000, Yamamoto et al., 2002). In this study, we immunostained FCMD brains with an antibody that recognizes the polysaccharide epitope of α-DG. Interestingly, the immunoreactivity of glycosylated α-DG in the subpial glia-limitans was not ubiquitously disrupted. On the other hand, hypoglycosylation of α-DG was suggested in hippocampal neurons of FCMD brains. This differential hypoglycosylation may provide a clue to understanding the pathological process in FCMD brains.
Section snippets
Results
The α-DG antibody labeled the glia-limitans at the cortical surface and the vessel walls in the control cerebrum (Fig. 1A) and cerebellum (Fig. 1D). In FCMD brains, the continuity of glia-limitans staining was occasionally interrupted at regions with parenchymal protrusions beyond the pial surface (Fig. 1B). Fragmentation of α-DG immunopositive membrane was also noted at the gyral fusion (Fig. 1C). In the FCMD cerebellum, immunostaining at the glia-limitans and vessel walls was comparable to
Discussion
The data presented here suggest co-expression of α-DG and fukutin in the hippocampal neurons of humans. Decreased labeling of α-DG with VIA4-1 in this cell population in FCMD brains supports the involvement of fukutin in the glycosylation process of α-DG, as is the case in skeletal muscle (Hayashi et al., 2001, Michele et al., 2002).
In recent years, α-DG expression in the glia-limitans has been highlighted, since it strongly supports the hypothesis that the fragile glia-limitans is essential to
Experimental procedures
Tissues from three FCMD patients (13–17 years old, M:F = 2:1) and three control subjects (all 14 years of age) were obtained at autopsy. Analysis of the fukutin gene revealed homozygous 3-kb insertions in all three FCMD patients. For immunohistochemistry, we took samples from the cerebral cortex, hippocampus, and cerebellum, and compared the results of FCMD cases with those of control subjects.
Mouse monoclonal antibody against α-DG (VIA4-1; Upstate Biochemistry, Lake Placid, NY, diluted 1:20)
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2023, Chinese Journal of Neurology