Advisory Committee Chair
Advisory Committee Members
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Alexander Disease (AxD) is a `gliopathy' caused by toxic, dominant gain-of-function mutations in the gene encoding glial fibrillary acidic protein (GFAP). Two distinct types of AxD exist. Type I AxD affected individuals develop cerebral symptoms by four years of age and generally suffer from macrocephaly, seizures, and physical and mental delays. As detection and diagnosis have improved, a larger portion, now about half of all AxD patients diagnosed, have onset >4 years and brainstem/spinal cord involvement. These type II AxD patients typically experience ataxia, palatal myoclonus, dysphagia and dysphonia. To date no study has examined a mechanistic link between the mutations in GFAP and the more caudal symptoms present in patients with type II AxD. Here we demonstrate that two key astrocytic functions, the ability to regulate both extracellular K+ and glutamate, are compromised in hindbrain regions and spinal cord in AxD mice. Spinal cord astrocytes in AxD transgenic mice are depolarized relative to wild type littermates, and have about a three-fold reduction in Ba2+-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. The loss of protein is associated with reduced mRNA expression of KCNJ10 and SLC1A2, the genes that code for Kir4.1 and GLT-1, respectively. Gene transcripts for each gene start to show differences at postnatal day 7 in AxD mice and never reach adult WT levels. Protein and mRNA reductions for both Kir4.1 and GLT-1 are exacerbated in AxD models that demonstrate earlier accumulation of GFAP and increased Rosenthal fiber formation, supporting the notion of GFAP toxicity. We propose these changes cause chronic dysregulation of K+ and glutamate, providing a mechanistic link between the GFAP mutations/overexpression and the resulting symptoms in those affected with type II AxD.
Minkel, Heather Renee, "Glial fibrillary acidic protein and gliosis: is GFAP more than a marker?" (2014). All ETDs from UAB. 2476.