Abstract
ABSTRACTCell and tissue degeneration, and the development of degenerative diseases, are influenced by genetic and environmental factors that affect protein misfolding and proteotoxicity. To better understand the role of the 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 that 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 the 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 (HSP), 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 that it serves an important role in muscle proteostasis and protection. Finally, studies of resistant leg muscles revealed that 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.
Highlights
Failure of proteostasis is implicated in a wide range of degenerative diseases
Comparison of flies exposed to a standard HS stress paradigm starting at either 1 or 7 days old and tested for their flight ability two days after the third exposure to HS [subjected to heat shock at 1 day old and analyzed at 4 days old (1d HS>4d) or subjected to heat shock at 7 days old and analyzed at 10 days old (7d HS>10d), respectively] demonstrated that young flies were strongly resistant to HS stress and retained the flight ability
These findings extend those of previous studies reporting loss of flight ability under HS stress (Krebs and Thompson, 2006) and formed the basis for analysis of the underlying cellular and molecular mechanisms
Summary
Failure of proteostasis is implicated in a wide range of degenerative diseases. As a protection mechanism against misfolded proteins in the cytoplasm, their presence triggers a HS response that includes expression of molecular chaperones to suppress proteotoxicity (Morimoto, 2012; Richter et al, 2010). Insufficient protection may contribute to degenerative disorders such as Parkinson’s and Alzheimer’s disease, hallmarks of which include failure of cellular proteostasis (Hipp et al, 2014; Labbadia and Morimoto, 2015a), cell-type susceptibility (Saxena and Caroni, 2011; Surmeier et al, 2012), dependence on environmental factors (Burbulla and Krüger, 2011; Cannon and Greenamyre, 2011; Goldman, 2014; Tanner et al, 2014) and onset with aging (Labbadia and Morimoto, 2015a; Taylor and Dillin, 2011). Of particular relevance to the present study are mechanisms of proteostasis involving clearance of misfolded and aggregated proteins (Vilchez et al, 2014) These proteins are often modified by ubiquitination, which can target them for degradation. Previous studies have shown that clearance of protein aggregates can be localized to the perinuclear compartment of the cell through microtubule-based transport (Mackeh et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
