Astrocytic expression of the chaperone DNAJB6 results in non-cell autonomous protection in Huntington’s disease

Abstract

Several neurodegenerative diseases like Huntington's, a polyglutamine (PolyQ) disease, are initiated by protein aggregation in neurons. Furthermore, these diseases are also associated with a multitude of responses in non-neuronal cells in the brain, in particular glial cells, like astrocytes. These non-neuronal responses have repeatedly been suggested to play a disease-modulating role, but how these may be exploited to delay the progression of neurodegeneration has remained unclear. Interestingly, one of the molecular changes that astrocytes undergo includes the upregulation of certain Heat Shock Proteins (HSPs) that are classically considered to maintain protein homeostasis, thus resulting in cell autonomous protection. Previously, we discovered DNAJB6, a member of the human DNAJ family, as potent cell autonomous suppressor of PolyQ aggregation and related neurodegeneration. Using cell type specific expression systems in D. melanogaster, we show that exclusive expression of DNAJB6 in astrocytes (that do not express PolyQ protein) can delay neurodegeneration and expands lifespan when the PolyQ protein is exclusively expressed in neurons (that do not co-express DNAJB6 themselves). This provides direct evidence for a non-cell autonomous protective role of astrocytes in PolyQ diseases.

Keywords

• Neurodegeneration
• Polyglutamine
• Aggregation
• Astrocytes
• Chaperones
• DNAJB6