P13 Investigating pathophysiology and therapeutic strategies in a mouse model of spinal and bulbar muscular atrophy (SBMA)

Abstract

to glycosylated epitopes on ADG. Loss of these glycans, specifically that identified by IIH6, is associated with a group of neuromuscular disorders collectively termed the dystroglycanopathies. Fukutin related protein (FKRP) is one of six determined/putative enzymes implicated in the glycosylation of ADG. We have previously generated a FKRP knock-down mouse which displays a hypoglycosylation of ADG and reduced laminin alpha 2 immunostaining at the muscle sarcolemma, the pial basement membrane and the inner limiting membrane (ILM) of the eye. Of particular interest is the absence of either IIH6 or laminin alpha 2 at the ILM in control or FKRP mice indicating that a novel ADG axis is involved at this basement membrane. In this paper we present evidence of an altered deposition of several laminin alpha chains in the eye and brain and suggest that multiple ligand interactions contribute to the pathogenesis of the dystroglycanopathies. Furthermore we have evidence indicating that DG interacts with laminin alpha 1 in the eye and the brain and that levels of laminin alpha 1 gene expression are up-regulated as a result of FKRP mediated hypoglycosylation of ADG.