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, the authors studied a mouse model of DM1 and brains of adult patients. They 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 they found to be the result of MBNL1 inactivation. GLT1 downregulation in DM1 astrocytes increases glutamate neurotoxicity and is detrimental to neurons. Finally, they demonstrated that the upregulation of GLT1 corrected Purkinje cell firing and motor incoordination in DM1 mice.
These findings show that glial defects are critical in DM1 brain pathophysiology and open promising therapeutic perspectives through the modulation of glutamate levels.
