Astrocytes and neurons produce distinct types of polyglucosan bodies in Lafora disease

Abstract

Lafora disease (LD), the most devastating adolescence-onset epilepsy, is caused by mutations in the EPM2A or EPM2B genes, which encode the proteins laforin and malin, respectively. Loss of function of one of these proteins, which are involved in the regulation of glycogen synthesis, induces the accumulation of polyglucosan bodies (PGBs)-known as Lafora bodies (LBs) and associated with neurons-in the brain. Ageing and some neurodegenerative conditions lead to the appearance of another type of PGB called corpora amylacea, which are associated with astrocytes and contain neo-epitopes that can be recognized by natural antibodies. Here we studied the PGBs in the cerebral cortex and hippocampus of malin knockout mice, a mouse model of LD. These animals presented not only LBs associated with neurons but also a significant number of PGBs associated with astrocytes. These astrocytic PGBs were also increased in mice from senescence-accelerated mouse-prone 8 (SAMP8) strain and mice with overexpression of Protein Targeting to Glycogen (PTG ), indicating that they are not exclusive of LD. The astrocytic PGBs, but not neuronal LBs, contained neo-epitopes that are recognized by natural antibodies. The astrocytic PGBs appeared predominantly in the hippocampus but were also present in some cortical brain regions, while neuronal LBs were found mainly in the brain cortex and the pyramidal layer of hippocampal regions CA2 and CA3. Our results indicate that astrocytes, contrary to current belief, are involved in the etiopathogenesis of LD.

Glycogen distribution in mouse hippocampus

“…The disappearance of the patchy pattern may be related to reported altered expression of glycogen metabolism‐related enzymes in aged mice (Drulis‐Fajdasz, Gizak, Wójtowicz, Wiśniewski, & Rakus, ) In many cases, ESG glycogen immunohistochemical signals in aged hippocampus become low with sporadic high‐signal spots reminiscent of polyglucosan bodies, which has been previously observed in neurons with PAS staining (Sinadinos et al, ). Of note, polyglucosan bodies were also visualized in astrocytes in Lafora disease model mice by glycogen immunohistochemistry (Augé et al, ).…”

A Potential Role for α-Amylase in Amyloid-β-Induced Astrocytic Glycogenolysis and Activation

“…Moreover, patients with AD commonly show an increased load of large abnormal aggregates of polysaccharides in astrocytes in form of polyglucosan bodies (PGB) or corpora amylacea [19][20][21]. These aggregates are thought to arise due to an imbalance between glycogenesis and glycogenolysis or an hyperphosphorylation of glycogen, which leads to the formation of poorly branched glycogen units with abnormal size [21][22][23]. The increased astrocytic PGB accumulation in AD patients thus indicates a disturbed astrocytic glycogenosis/glycogenolysis balance in these patients.…”

Neuron-Glia Interactions in Neurodevelopmental Disorders

“…PGB has been studied in neurons for a long time, but the fact that astrocytes also have a considerable portion of PGBs is a recent discovery. Astrocytic PGBs are significantly increased in malin KO mice, indicating that astrocytic PGB could also cause LD [ 90 , 169 ]. Therefore, further studies on neuron-glia interactions and pathogenesis are required using this genetic model of epilepsy.…”