Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from t...

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Bibliographic Details
Published in:Brain (London, England : 1878) England : 1878), 2021-09, Vol.144 (8), p.2349-2360
Main Authors: Duran, Jordi, Hervera, Arnau, Markussen, Kia H, Varea, Olga, López-Soldado, Iliana, Sun, Ramon C, Del Río, Jose Antonio, Gentry, Matthew S, Guinovart, Joan J
Format: Article
Language:English
Subjects:
Animals
Astrocytes - metabolism
Astrocytes - pathology
Brain - metabolism
Brain - pathology
Disease Models, Animal
Glycogen - metabolism
Glycogen Synthase - genetics
Glycogen Synthase - metabolism
Lafora Disease - genetics
Lafora Disease - metabolism
Lafora Disease - pathology
Mice
Mice, Knockout
Nerve Degeneration - genetics
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Neurons - metabolism
Neurons - pathology
Original
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary:The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes-thus impeding Lafora bodies accumulation in this cell type-prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that over-accumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.
ISSN:0006-8950
1460-2156
DOI:10.1093/brain/awab110