Title: Myelin deficits in a rat model of Alexander disease
Legend: (A) Cervical spinal cord cross sections from the Gfap+/R237H rat model of Alexander disease (R237H) are smaller in total area compared to wild-type rats (WT), but specifically show reduced white matter. (B) Quantification of myelin basic protein (MBP), one of the major myelin proteins, demonstrates reduced expression of all isoforms in R237H rats. (C) Electron microscopy shows myelin sheaths are thinner in R237H rats, and axons exhibit signs of degeneration with accumulating organelles (arrows), dark cytoplasm (asterisk), and empty sheaths (hash symbol) in the dorsal corticospinal tract.
Citation: Hagemann TL, Powers B, Lin NH, Mohamed AF, Dague KL, Hannah SC, Bachmann G, Mazur C, Rigo F, Olsen AL, Feany MB, Perng MD, Berman RF, Messing A (2021) Antisense therapy in a rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment. Science Translational Medicine 13:eabg4711.
Abstract: Alexander disease (AxD) is a devastating leukodystrophy caused by gain-of-function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report, we introduce a rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, wide-spread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with about 14% dying of unknown cause between 6 and 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long-lasting suppression, reverses GFAP pathology, and, depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. In this report, we characterize an improved animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease, and use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease.
About the Lab: Our research focuses on the role of astrocytes in neurodegenerative disease and the cellular consequences of their dysfunction. Astrocytes have traditionally been thought of as support cells that maintain ion and neurotransmitter homeostasis in the central nervous system (CNS). However, research over the past few decades has revealed more complex functions including the regulation of neurogenesis, synaptogenesis, neurotransmission and remyelination. In addition, astrocytes control blood flow, maintain the blood brain barrier, and contribute to the distribution and clearance of compounds through the CNS glymphatic system.
Astrocytes take on another critical role of reacting to CNS injury by activating anti-stress and neuroinflammatory pathways in both acute insults and chronic disease. Reactive astrocytes are heterogeneous in their response and can either promote or prevent regeneration and repair. Given the complexities of astrocyte function in the healthy CNS and their sometimes paradoxical role in brain and spinal cord injury, it can be difficult to dissect the effects of astrogliosis on other neural cell types from the primary insult.
To better understand astrocyte function in neurodegenerative disease, we have focused on one of the few examples of a primary disorder of astrocytes, Alexander disease. Alexander disease (AxD) is caused by mutations in the gene for glial fibrillary acidic protein (GFAP), an astrocyte specific intermediate filament protein, that lead to protein aggregation, activation of stress response genes, including GFAP, and reactive gliosis. AxD can affect all ages but is most severe in children, who often present with seizures, motor and cognitive delay, and a general failure to thrive. We have generated several rodent models with missense mutations homologous to those found in patients with the disease. These models allow us to study the effects of astrocyte dysfunction on other cell types in the mammalian CNS, including neurons and oligodendrocytes and their progenitors. As with other injuries, the astrocyte response to mutant GFAP is also heterogeneous, and a second goal is to identify the molecular networks controlling regional differences in astrocyte reactivity. Finally we hope that understanding the mechanisms behind Alexander disease pathology will lead to therapeutic strategies for this devastating disorder as well as other diseases with astropathology.