Dystroglycan in the Cerebellum is a Laminin α2‐chain Binding Protein at the Glial‐Vascular Interface and is Expressed in Purkinje cells

Abstract

Dystroglycan is a core component of the dystrophin receptor complex in skeletal muscle which links the extracellular matrix to the muscle cytoskeleton. Dystrophin, dystrophin-related protein (DRP, utrophin) and dystroglycan are present not only in muscles but also in the brain. Dystrophin is expressed in certain neuronal populations while DRP is associated with perivascular astrocytes. To gain insights into the function and molecular interactions of dystroglycan in the brain, we examined the localization of alpha- and beta-dystroglycan at the cellular and subcellular levels in the rat cerebellum. In blood vessels, we find alpha-dystroglycan associated with the laminin alpha 2-chain-rich parenchymal vascular basement membrane and beta-dystroglycan associated with the endfeet of perivascular astrocytes. We also show that alpha-dystroglycan purified from the brain binds alpha 2-chain-containing laminin-2. These observations suggest a dystroglycan-mediated linkage between DRP in perivascular astrocytic endfeet and laminin-2 in the parenchymal basement membrane similar to that described in skeletal muscle. This linkage of the astrocytic endfeet to the vascular basement membrane is likely to be important for blood vessel formation and stabilization and for maintaining the integrity of the blood-brain barrier. In addition to blood vessel labelling, we show that alpha-dystroglycan in the rat cerebellum is associated with the surface of Purkinje cell bodies, dendrites and dendritic spines. Dystrophin has previously been localized to the inner surface of the plasma membrane of Purkinje cells and is enriched at postsynaptic sites. Thus, the present results also support the hypothesis that dystrophin interacts with dystroglycan in cerebellar Purkinje neurons.

Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy

“…Dystrophin products localized to neurons are only found in the soma and dendrites (not the axon) and tend to aggregate at the postsynaptic densities, suggesting a possible role in synaptic function (Dorbani-Mamine et al, 1998;Jancsik & Hajos, 1998;Kim et al, 1992;Lidov et al, 1990;Uchino et al, 1994a). Further, dystrophin products in the central nervous system are found more in the cerebral and cerebellar cortices than in lower brain structures (Gorecki et al, 1998(Gorecki et al, ,1992Kimura et al, 1997;Lidov et al, 1990;Tian et al, 1996;Uchino et al, 1994a,b), and various theories of the neuroanatomical basis of working memory and/or attention have localized these abilities to cortical areas (Baddeley, 1986;Goldman-Rakic, 1988;Mesulam, 1990;Posner & Peterson, 1990). Future neurobiological work examining the role of dystrophin in the development of the brain may offer greater insight into the neurological basis of verbal working memory.…”

“…In human DMD autopsy tissue and in mouse models of DMD, no brain dystrophin has been found. In normal brain tissue, however, different forms of brain dystrophin have been localized both to specific cell types, as well as to specific brain regions (Gorecki et al, 1992(Gorecki et al, ,1998Kimura et al, 1997;Lidov et al, 1990;Tian et al, 1996;Uchino et al, 1994a,b). One type is localized specifically to the pyramidal cells of the cerebral cortex and the hippocampus, and does not appear to localize to lower brain structures.…”

Duchenne muscular dystrophy: alpha-dystroglycan immunoexpression in skeletal muscle and cognitive performance

“…We can speculate on the α-DG's role in the CNS, and in cognitive performance because it locates itself in neurons at the same distribution as dystrophin 9 which are found in the neurons of the pyramidal cells, cerebral cortex and in the Purkinje cells from the cerebellum and regions CA1-CA3 of hippocampus 16,31 ; amongst other places such as the astrocytes found in the cerebral white matter and sensory neurons and motoneurons in the ventral and dorsal columns 32 .…”

Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy

“…Brain dystrophins are found primarily in the cortex rather than in lower brain structures, and they have been localized to specific cell types as well. In neurons, it has been most clearly identified in pyramidal, stellate, and Purkinje cells (Gorecki et al, 1992;Lidov, Byers, Watkins, & Kunkel, 1990;Tian et al, 1996;, and appears to be concentrated primarily in the post-synaptic region (Jancsik & Hajos, 1998;Kim, Wu, Xu, & Black, 1992). Although the contribution of the dystrophin brain products to brain function is unknown, they have been hypothesized to play a structural role that aids in synaptic transmission (e.g., Jancsik & Hajos, 1998).…”