Alexander's Disease: Potential Drug Targets and Future Directions

Abstract

Alexander's disease is a rare neurodegenerative disorder primarily characterized by upregulation of the GFAP gene and the formation of Rosenthal fibers. Its prognosis is fatal, with limited treatment options currently available. The GFAP protein is a marker for mature astrocytes. It results in the upregulation of reactive astroglioses. Reactive astroglioses is a neuroprotective condition that, when functioning correctly, helps protect the brain from stress and injury and prevents further injury. However, unregulated reactive astroglioses is linked with many neurodegenerative diseases. Due to the relative rarity in the incidence of AxD, treatment options have not been as widely investigated. This review explores potential drug targets that may impact GFAP gene expression, such as STAT3, GDNF, NF-kB, LCN-2, and the LPS pathway. These drug targets have previously been or are currently being explored in other neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. The only treatment option currently in clinical trial phases involves methods to induce the knockout of the GFAP gene. Due to GFAP's neuroprotective role in brain injury and stress, it is important to explore alternative treatment options that downregulate GFAP as opposed to shutting it off entirely.

Keywords: Alexander’s; Astrocytes; AxD; GFAP; Neurodegenerative; Treatment.

Fig. 1

A summary of AxD pathology; connection between observed impact and their corresponding clinical presentation. A mutation occurs in variable locations on the GFAP protein, resulting in the following direct and observed results: altered intermediate filament assembly, Rosenthal fiber formation, and upregulation of GFAP and its respective regulatory genes. As a result, astrocyte function and myelin formation are disturbed, and reactive astrogliosis is upregulated. This results in white matter degeneration and brain tissue damage. These account for the symptoms observed in individuals with AxD, such as coordination problems and developmental delays. All these  outcomes compound to further contribute to neurodegeneration, which in turn further exacerbates these issues

Fig. 2

Interactions between the potential drug targets for AxD. Activated STAT3 contributes to reactive astroglioses, LPS pathway, and LCN-2 and upregulates GFAP. NF-kB is upregulated by and upregulates the LPS pathway and STAT3. LCN-2 upregulates NF-kB and upregulates GFAP itself. Lipocalin, LCN-2, is upregulated by the LPS pathway and STAT3 and upregulated by and upregulates GFAP itself. GDNF has a neuroprotective role and decreases reactive astroglioses. It can both upregulate and downregulate GFAP, depending on conditions