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.
Anterior vertebral body tethering (AVBT), or spinal growth tethering, is an emerging technology that recently received Food and Drug Administration (FDA) approval through a humanitarian device exemption designation to treat idiopathic scoliosis patients with remaining growth. This study compared patients who underwent AVBT with those treated with standard-of-care posterior spinal fusion (PSF) to determine inherent differences in patients and families who seek cutting-edge treatments. The authors reviewed 62 PSF patients from a multicenter registry and 20 AVBT patients from an FDA-approved investigational clinical trial. The authors examined demographics, preoperative clinical and radiographic variables, and health-related quality of life (HRQOL). All included patients preoperatively were classified as Lenke type 1 or 2 with a thoracic curve of 35° to 60°, a lumbar curve less than 35°, and a skeletal maturity score of Risser sign 0 or Sanders bone age of 4 or less. Idiopathic scoliosis patients treated with surgical intervention were primarily White females who were 12 years old. No differences in demographics, clinical variables, and radiographic measures were detected between the PSF and AVBT cohorts. The AVBT group showed more thoracic flexibility on bending radiographs, correcting on average 59% compared with 43% for PSF patients (
P
=.005). Patients had similar HRQOL total scores and scores across each of the 5 domains of the Scoliosis Research Society Questionnaire Version 22. The percentage of patients scoring below 4.0 within each domain was comparable between cohorts. Scoliosis patients who underwent vertebral tethering at a level of deformity magnitude and maturity similar to those who underwent posterior fusion did not differ at baseline regarding demographics, clinical variables, and HRQOL. [
Orthopedics
. 2021;44(1):24–28.]
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