Abstract
In brain, glycogen metabolism is predominantly restricted to astrocytes but it also indirectly supports neuronal functions. Increased accumulation of glycogen in neurons is mysteriously pathogenic triggering neurodegeneration as seen in “Lafora disease” (LD) and in other transgenic animal models of neuronal glycogen accumulation. LD is a fatal neurodegenerative disorder with excessive glycogen inclusions in neurons. Autophagy, a pathway for bulk degradation of obsolete cellular constituents also degrades metabolites like lipid and glycogen. Recently, defects in this pathway emerged as a plausible reason for glycogen accumulation in neurons in LD, although some contradictions prevail. Albeit surprising, a reciprocal regulation of autophagy by glycogen in neurons has also just been proposed. Notably, increasing evidences of interaction between proteins of autophagy and glycogen metabolism from diverse model systems indicate a conserved, dynamic, and regulatory cross-talk between these two pathways. Concerning these findings, we herein provide certain models for the molecular basis of this cross-talk and discuss its potential implication in the pathophysiology of LD.
Highlights
A common feature of many neurodegenerative disorders is the defect in protein quality control mechanisms including ubiquitin proteasome system (UPS) and macroautophagy leading to biogenesis and accumulation of protein aggregates or inclusions [1]
Glycogen or glycogen like inclusions called polyglucosan bodies, do accumulate in neurons in (a) pathologies like Pompe disease [5], Lafora disease (LD) [6], Alzheimer’s disease (AD) [7] amyotrophic lateral sclerosis [8], adult polyglucosan body disease (APBD) [9], (b) under pathophysiological conditions like diabetes [10], hypoxia [11], and during aging [9]. This accumulation correlates with neurodegeneration in Pompe disease [5], in LD [6], in fly/mouse models expressing constitutive active glycogen synthase (GS) in neurons [12], and with reduced neuronal functions during aging [13]
Autophagy-related gene (Atg)-deficient mice could be beneficial in investigating the status of neuronal glycogen metabolism
Summary
A common feature of many neurodegenerative disorders is the defect in protein quality control mechanisms including ubiquitin proteasome system (UPS) and macroautophagy (hereafter referred as autophagy) leading to biogenesis and accumulation of protein aggregates or inclusions [1]. Glycogen or glycogen like inclusions called polyglucosan bodies, do accumulate in neurons in (a) pathologies like Pompe disease [5], Lafora disease (LD) [6], Alzheimer’s disease (AD) [7] amyotrophic lateral sclerosis [8], adult polyglucosan body disease (APBD) [9], (b) under pathophysiological conditions like diabetes [10], hypoxia [11], and during aging [9] This accumulation correlates with neurodegeneration in Pompe disease [5], in LD [6], in fly/mouse models expressing constitutive active glycogen synthase (GS) in neurons [12], and with reduced neuronal functions during aging [13]. NEURONAL GLYCOGEN METABOLISM: GROWING UNDERSTANDING FROM A RARE EPILEPSY – “LAFORA DISEASE” During the last decade, understanding the pathophysiological mechanism of a rare progressive myoclonus epilepsy “LD” has www.frontiersin.org
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