TY - JOUR
T1 - Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease
AU - Duran, Jordi
AU - Hervera, Arnau
AU - Markussen, Kia H.
AU - Varea, Olga
AU - López-Soldado, Iliana
AU - Sun, Ramon
AU - Del Río, Jose Antonio
AU - Gentry, Matthew S.
AU - Guinovart, Joan J.
N1 - Publisher Copyright:
© 2021 The Author(s) (2021).
PY - 2021/8/1
Y1 - 2021/8/1
N2 - 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.
AB - 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.
KW - Epilepsy
KW - Glycogen
KW - Lafora disease
KW - Neurodegeneration
KW - Neuroinflammation
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UR - http://www.scopus.com/inward/citedby.url?scp=85111032050&partnerID=8YFLogxK
U2 - 10.1093/brain/awab110
DO - 10.1093/brain/awab110
M3 - Article
C2 - 33822008
AN - SCOPUS:85111032050
SN - 0006-8950
VL - 144
SP - 2349
EP - 2360
JO - Brain
JF - Brain
IS - 8
ER -