The role of GFAP mutation in Alexander disease

Abstract

Alexaneder disease (AxD) is a primary genetic disorder of astrocyte caused by mutations in the type 111 intermediate filament (IF) glial fibrillary acidic protein (GFAP). The pathological hallmark of this disease is the presence of Rosenthal fibres (RF), ubiquitinated protein aggregates with GFAP being the primary constituent. On the basis of age at onset, the disease has been divided into three subtypes: infantile, juvenile and adult. Whilst one of the common mutations R416W is reported in AxD with a wide range in disease severity and age of onset, the mechanisms by which this mutation leads to AxD remain unknown. To investigate the role of mutated protein in the disease process, I have developed a cell model system in which the expression of GFAP can be regulated by doxycycline. Expression of R416W GFAP leads to aggregate formation, which increases small heat shock protein (sHSP) expression, activates stress-activated protein kinase (SAPK) pathways and partially impairs proteosome function. This is accompanied by the sequestration of sHSPs and activated SAPK into GFAP-containing aggregates, which make cells more susceptible to stress. However, R416W mutation was found to not always disrupt the endogenous Ifs, but to incorporate into GFAP networks when expressed at low levels. The potential functional impact of incorporating low level of the disease-causing GFAP mutant into the pre-exiting GFAP networks is that cells respond poorly to stressful conditions. These data provide direct evidence to suggest that astrocyte dysfunction play a key role in the development of AxD and stress is likely to have the most influence on the presence and progression of the disease.