Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

Jordi Duran, Arnau Hervera, Kia H. Markussen, Olga Varea, Iliana López-Soldado, Ramon Sun, Jose Antonio Del Río, Matthew S. Gentry, Joan J. Guinovart

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2349-2360
Number of pages12
JournalBrain
Volume144
Issue number8
DOIs
StatePublished - Aug 1 2021

Bibliographical note

Funding Information:
IRB Barcelona and IBEC are the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain). This study was supported by grants from MINECO (BFU2017-84345-P to J.D. and J.J.G. and RTI2018-099773-B-I00 to J.A.D. and A.H.), the CIBER de Diabetes y Enfermedades Metabólicas Asociadas (ISCIII, Ministerio de Ciencia e Innovación), a grant from the National Institutes of Health (NIH-NINDS) (P01 NS097197) to J.J.G. and M.S.G., NIH grant R35 NS116824 to M.S.G., and NIH grant R01 AG066653 to R.C.S. The project leading to these results also received funding from 'la Caixa' Foundation (ID 100010434) under the agreement LCF/PR/ HR19/52160007 with J.A.D.

Publisher Copyright:
© 2021 The Author(s) (2021).

Keywords

  • Epilepsy
  • Glycogen
  • Lafora disease
  • Neurodegeneration
  • Neuroinflammation

ASJC Scopus subject areas

  • Medicine (all)

Fingerprint

Dive into the research topics of 'Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease'. Together they form a unique fingerprint.

Cite this