RRC ID 47664
Author Kawasaki F, Koonce NL, Guo L, Fatima S, Qiu C, Moon MT, Zheng Y, Ordway RW.
Title Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration.
Journal Dis Model Mech
Abstract Cell 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.
Volume 9(9)
Pages 953-64
Published 2016-9-1
DOI 10.1242/dmm.026385
PII dmm.026385
PMID 27483356
PMC PMC5047692
MeSH Aging / physiology Animals Axons / pathology Cell Nucleus / metabolism Disease Models, Animal Drosophila Proteins / metabolism* Drosophila melanogaster / physiology* Environment* Flight, Animal Heat-Shock Proteins, Small / metabolism* Heat-Shock Response Microtubules / metabolism Muscle Fibers, Skeletal / pathology Neuroglia / pathology Protein Aggregates Stress, Physiological* Ubiquitin / metabolism
IF 4.651
Times Cited 10
Drosophila DGRC#140400