Elevated GFAP induces astrocyte dysfunction in caudal brain regions: A potential mechanism for hindbrain involved symptoms in type II Alexander disease
- 17 July 2015
- Vol. 63 (12), 2285-2297
- https://doi.org/10.1002/glia.22893
Abstract
Alexander Disease (AxD) is a "gliopathy" caused by toxic, dominant gain-of-function mutations in the glial fibrillary acidic protein (GFAP) gene. Two distinct types of AxD exist. Type I AxD affected individuals develop cerebral symptoms by 4 years of age and suffer from macrocephaly, seizures, and physical and mental delays. As detection and diagnosis have improved, approximately half of all AxD patients diagnosed have onset >4 years and brainstem/spinal cord involvement. Type II AxD patients experience ataxia, palatal myoclonus, dysphagia, and dysphonia. No study has examined a mechanistic link between the GFAP mutations and caudal symptoms present in type II AxD patients. We demonstrate that two key astrocytic functions, the ability to regulate extracellular glutamate and to take up K(+) via K+ channels, are compromised in hindbrain regions and spinal cord in AxD mice. Spinal cord astrocytes in AxD transgenic mice are depolarized relative to WT littermates, and have a three-fold reduction in Ba(2+) -sensitive Kir4.1 mediated currents and six-fold reduction in glutamate uptake currents. The loss of these two functions is due to significant decreases in Kir4.1 (>70%) and GLT-1 (>60%) protein expression. mRNA expression for KCNJ10 and SLC1A2, the genes that code for Kir4.1 and GLT-1, are significantly reduced by postnatal Day 7. Protein and mRNA reductions for Kir4.1 and GLT-1 are exacerbated in AxD models that demonstrate earlier accumulation of GFAP and increased Rosenthal fiber formation. These findings provide a mechanistic link between the GFAP mutations/overexpression and the symptoms in those affected with Type II AxD.Keywords
Funding Information
- NINDS (R01NS075062, P01NS42803)
This publication has 65 references indexed in Scilit:
- GFAP Expression as an Indicator of Disease Severity in Mouse Models of Alexander DiseaseASN Neuro, 2013
- Gains or losses: molecular mechanisms of TDP43-mediated neurodegenerationNature Reviews Neuroscience, 2011
- Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43Nature Neuroscience, 2011
- Molecular comparison of GLT1+ and ALDH1L1+ astrocytes in vivo in astroglial reporter miceGlia, 2010
- Variable loss of Kir4.1 channel function in SeSAME syndrome mutationsBiochemical and Biophysical Research Communications, 2010
- Alteration of glial-neuronal metabolic interactions in a mouse model of Alexander diseaseGlia, 2010
- Epilepsy, Ataxia, Sensorineural Deafness, Tubulopathy, andKCNJ10MutationsThe New England Journal of Medicine, 2009
- Properties of astrocytes cultured from GFAP over-expressing and GFAP mutant miceExperimental Cell Research, 2009
- Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10Proceedings of the National Academy of Sciences of the United States of America, 2009
- Genome-wide atlas of gene expression in the adult mouse brainNature, 2006