Cell and tissue degeneration and the development of degenerative disease are influenced by genetic and environmental factors which affect protein misfolding and proteotoxicity. To better understand the role of environment in degeneration, we developed a genetic model for heat shock (HS) stress-induced degeneration in Drosophila. This model exhibits a unique combination of features which enhance genetic analysis of degeneration and protection mechanisms involving environmental stress. These include cell type-specific failure of proteostasis and degeneration in response to global stress, cell-nonautonomous interactions within a simple and accessible network of susceptible cell types, and precise temporal control over the induction of degeneration. In wild-type flies, HS stress causes selective loss of flight ability and degeneration of three susceptible cell types comprising the flight motor: muscle, motor neurons and associated glia. Other motor behaviors persist and, accordingly, the corresponding cell types controlling leg motor function are resistant to degeneration. Flight motor degeneration was preceded by a failure of muscle proteostasis characterized by diffuse ubiquitinated protein aggregates. Moreover, muscle-specific overexpression of a small heat shock protein, HSP23, promoted proteostasis and protected muscle from HS stress. Notably, neurons and glia were protected as well, indicating that a small HSP can mediate cell-nonautonomous protection. Cell-autonomous protection of muscle was characterized by a distinct distribution of ubiquitinated proteins, including perinuclear localization and clearance of protein aggregates associated with the perinuclear microtubule network. This network was severely disrupted in wild-type preparations prior to degeneration, suggesting it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed they sustain proteostasis and the microtubule cytoskeleton after HS stress. These findings establish a model for genetic analysis of degeneration and protection mechanisms involving contributions of environmental factors and advance our understanding of the protective functions and therapeutic potential of small HSPs.
- Received May 22, 2016.
- Accepted July 5, 2016.
- © 2016. Published by The Company of Biologists Ltd
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