Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease

Abstract

Lafora disease (LD) is caused by mutations in either the laforin or malin gene. The hallmark of the disease is the accumulation of polyglucosan inclusions called Lafora Bodies (LBs). Malin knockout (KO) mice present polyglucosan accumulations in several brain areas, as do patients of LD. These structures are abundant in the cerebellum and hippocampus. Here, we report a large increase in glycogen synthase (GS) in these mice, in which the enzyme accumulates in LBs. Our study focused on the hippocampus where, under physiological conditions, astrocytes and parvalbumin-positive (PV+) interneurons expressed GS and malin. Although LBs have been described only in neurons, we found this polyglucosan accumulation in the astrocytes of the KO mice. They also had LBs in the soma and some processes of PV+ interneurons. This phenomenon was accompanied by the progressive loss of these neuronal cells and, importantly, neurophysiological alterations potentially related to impairment of hippocampal function. Our results emphasize the relevance of the laforin–malin complex in the control of glycogen metabolism and highlight altered glycogen accumulation as a key contributor to neurodegeneration in LD.

Neuronatin-mediated Aberrant Calcium Signaling and Endoplasmic Reticulum Stress Underlie Neuropathology in Lafora Disease

“…Excessive accumulation of neuronatin could potentially lead to the degeneration of these inhibitory interneurons in LD brain by disturbing Ca 2ϩ homeostasis and inducing ER stress. Our findings are very similar with a recent report that demonstrates progressive degeneration of PVϩve GABAergic interneuron in the hippocampus of malin knock-out mice (23). The loss of PVϩve inhibitory interneurons in LD brain could potentially explain the rapidly progressing seizures and myoclonus in this disease.…”

“…Knock-out mice for both laforin and malin also exhibits progressive accumulation of Lafora bodies in various tissues including brain, defects in autophagic degradation pathway, and widespread neurodegeneration (17,18,(21)(22)(23)(24). Current finding in LD mice models point toward the role of abnormal accumulation of Lafora bodies (18,23,25) and impairment of intracellular protein degradation pathways (17,18,26) in the disease pathogenesis. Lafora bodies in the brain are also associated with a number of cellular factors including the compo-* This work was supported in part by a core grant from the Department of Biotechnology to National Brain Research Centre, Government of India, and Extramural Grant BT/PR13590/MED/30/286/2009 from the Department of Biotechnology, Government of India.…”

Increased Laforin and Laforin Binding to Glycogen Underlie Lafora Body Formation in Malin-deficient Lafora Disease

“…When GS activity was measured in tissues of 9 -12-month-old Epm2a Ϫ/Ϫ and Epm2b Ϫ/Ϫ animals, no increase was found. However, GS protein was vastly increased, and this increase segregated with a low speed (10,000 ϫ g centrifugation) pellet (LSP), which contained the LB (2,29). Similar measurements taken at 3 months, when LB were less than at 9 -12 months, also showed increased GS in the LSP (26).…”

“…One was that increased GS activity does not underlie polyglucosan generation and that the increased GS protein in the LSP is GS trapped with precipitated glycogen and polyglucosans (2). The alternative view was that the cell culture results combined with the great increase in polyglucosan-associated GS in mouse tissues confirm the role of increased GS in polyglucosan formation (29). To resolve this controversy, we measured GS protein and activity in young 1 month-old Epm2b Ϫ/Ϫ mice, which do not have detectable LB (in these young mice, glycogen quantity and branching are also still normal) (Fig.…”

Deficiency of a Glycogen Synthase-associated Protein, Epm2aip1, Causes Decreased Glycogen Synthesis and Hepatic Insulin Resistance

“…The results to date support two main hypotheses. 1) The laforin-malin complex regulates PTG and GS, and the absence of laforin or malin leads to increased GS activity, excessive elongation of glycogen strands, and conversion of GS to polyglucosan (16,17).…”