Non-apoptotic caspase activity in neurons Caspases are a family of conserved cysteine proteases that orchestrate apoptotic and pyroptotic cell death. Caspase activity is robustly induced shortly before cell death, and caspase-deficient animals have excess cell numbers. Therefore, activation of caspases is often assumed to represent a commitment point towards cell death. However, mounting evidence indicates that caspases also have non-apoptotic roles in healthy cells and tissues. Mammalian and Drosophila neurons have been reported to use caspases for pruning axonal and dendritic process, which is essential for functional neural networks, potentially by similar mechanisms as apoptosis except spatially restricted. However, fly and mammalian caspases have been implicated in a range of other cellular processes, including cell proliferation and differentiation. Caspase activation has been detected in growing axon terminals, and without evidence of cell death. However, the key unanswered questions remain, including what types of neurons display caspase activity and when. Furthermore, very little is known about the non- apoptotic functions of caspase activity in healthy neurons. A number of different caspase biosensors have been developed to detect caspase activation in neurons and other cell types, however available caspase biosensors are not sufficiently sensitive or sustained to address these questions. Therefore, we developed a new dual color caspase biosensor for Drosophila to detect and study non-apoptotic caspase activity in neurons. We propose to determine which neurons exhibit non-apoptotic caspase, and to establish a role for caspases in normal neuronal function. These studies are needed to gain new insights into the mechanisms that connect the normal versus death functions of caspases, as dysregulation of this balance could contribute importantly to neurodegeneration.

Public Health Relevance

Caspase family proteases can kill cells by apoptosis, but can also have important functions in normal healthy neurons. This balance between normal and death functions may impact neurodegenerative processes. Using a caspase biosensor, we will study the role of caspases in normal neuronal function required for detecting odors in Drosophila.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Gubitz, Amelie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Public Health
United States
Zip Code
Aouacheria, Abdel; Cunningham, Kyle W; Hardwick, J Marie et al. (2018) Comment on ""Sterilizing immunity in the lung relies on targeting fungal apoptosis-like programmed cell death"". Science 360:
Hardwick, J Marie (2018) Do Fungi Undergo Apoptosis-Like Programmed Cell Death? MBio 9:
Metz, Kyle A; Teng, Xinchen; Coppens, Isabelle et al. (2018) KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect. Ann Neurol 84:766-780
White, Kristin; Arama, Eli; Hardwick, J Marie (2017) Controlling caspase activity in life and death. PLoS Genet 13:e1006545
Aouacheria, Abdel; Baghdiguian, Stephen; Lamb, Heather M et al. (2017) Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins. Neurochem Int 109:141-161
Tang, Ho Lam; Tang, Ho Man; Fung, Ming Chiu et al. (2016) In Vivo Biosensor Tracks Non-apoptotic Caspase Activity in Drosophila. J Vis Exp :
Tang, Ho Lam; Tang, Ho Man; Fung, Ming Chiu et al. (2015) In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Sci Rep 5:9015