Small heat shock proteins mediate cell-autonomous and -nonautonomous protection in a Drosophila model for environmental-stress-induced degeneration

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

Differential adhesion regulates neurite placement via a retrograde zippering mechanism

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Sengupta, T., Koonce, N. L., Vazquez-Martinez, N., Moyle, M. W., Duncan, L. H., Emerson, S. E., Han, X., Shao, L., Wu, Y., Santella, A., Fan, L., Bao, Z., Mohler, W. A., Shroff, H., & Colon-Ramos, D. A. Differential adhesion regulates neurite placement via a retrograde zippering mechanism. Elife, 10, (2021): e71171, https://doi.org/10.7554/eLife.71171.During development, neurites and synapses segregate into specific neighborhoods or layers within nerve bundles. The developmental programs guiding placement of neurites in specific layers, and hence their incorporation into specific circuits, are not well understood. We implement novel imaging methods and quantitative models to document the embryonic development of the C. elegans brain neuropil, and discover that differential adhesion mechanisms control precise placement of single neurites onto specific layers. Differential adhesion is orchestrated via developmentally regulated expression of the IgCAM SYG-1, and its partner ligand SYG-2. Changes in SYG-1 expression across neuropil layers result in changes in adhesive forces, which sort SYG-2-expressing neurons. Sorting to layers occurs, not via outgrowth from the neurite tip, but via an alternate mechanism of retrograde zippering, involving interactions between neurite shafts. Our study indicates that biophysical principles from differential adhesion govern neurite placement and synaptic specificity in vivo in developing neuropil bundles.National Institutes of Health (R24-OD01647) Zhirong Bao William Mohler Daniel A Colón-Ramos National Institutes of Health (R01NS076558) Daniel A Colón-Ramos National Institutes of Health (DP1NS111778) Daniel A Colón-Ramos Howard Hughes Medical Institute (Faculty Scholar Award) Daniel A Colón-Ramos Marine Biological Laboratory (Whitman and Fellows program) Hari Shroff Daniel A Colón-Ramos Gordon and Betty Moore Foundation (Moore Grant) Hari Shroff Daniel A Colón-Ramos Gruber Foundation (Gruber Science Fellowship) Titas Sengupta National Institutes of Health (Predoctoral Training Program in Genetics NIH 2020 T32 GM.) Noelle L Koonce National Institutes of Health (F32-NS098616) Mark W Moyle National Institutes of Health (NIBIB Intramural Research Program) Hari Shroff National Institutes of Health (P30CA008748) Zhirong Ba