Journal
CELL REPORTS
Volume 19, Issue 13, Pages 2718-2729Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.06.006
Keywords
-
Categories
Funding
- AFM-Telethon (France) [16161]
- INSERM (France)
- Universite Paris Descartes (France)
- Fondation ARC (France)
- Ministere Francais de la Recherche et Technologie (France)
- Imagine Foundation
- National Research Agency [ANR-10-IAHU-01, ANR-10BLAN-1121-01]
Ask authors/readers for more resources
Brain function is compromised in myotonic dystrophy type 1 (DM1), but the underlying mechanisms are not fully understood. To gain insight into the cellular and molecular pathways primarily affected, we studied a mouse model of DM1 and brains of adult patients. We found pronounced RNA toxicity in the Bergmann glia of the cerebellum, in association with abnormal Purkinje cell firing and fine motor incoordination in DM1 mice. A global proteomics approach revealed downregulation of the GLT1 glutamate transporter in DM1 mice and human patients, which we found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, we demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice. Our findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available