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Several neurodegenerative diseases like Huntington’s disease are initiated by protein aggregation in neurons. 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 been repeatedly 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. The aim of this thesis was to explore how a specific HSP not only may provide protection when expressed in the neurons (cell autonomous protection), but also if and how it might be neuroprotective when exclusively expressed in astrocytes (non-cell autonomous protection). To test this, we developed a Drosophila melanogaster model system for Huntington’s disease and used DNAJB6, a potent cell autonomous protective HSP against huntingtin-related neurodegeneration. We show that expression of DNAJB6 in neurons protects against huntingtin aggregation in the brain and delays the onset of degeneration. When expressed in astrocytes DNAJB6 also delays the onset of neurodegeneration, but not by reducing aggregate load in the brain. Rather, our data suggest that DNAJB6 keeps astrocytes fit to take over the aggregate burden from the affected neurons, such that neighboring neurons are spared from the so-called spreading of aggregates throughout the brain.

Cell-autonomous and non-cell autonomous protection of DNAJB6 in Huntington’s disease