SARM1 is responsible for calpain-dependent dendrite degeneration in mouse hippocampal neurons

Miyamoto, Takashi; Kim, Chaeyoung; Chow, Johann; Dugas, Jason C.; DeGroot, Jack; Bagdasarian, Alex L.; Thottumkara, Arun P.; Larhammar, Martin; Calvert, Meredith EK.; Fox, Brian M.; Lewcock, Joseph W.; Kane, Lesley A.

doi:10.1016/j.jbc.2024.105630

Cited by 2 publications

References 65 publications

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Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models

Chin,

Joy,

Samaddar

et al. 2024

Preprint

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Mitochondria undergo dynamic morphological changes depending on cellular cues, stress, genetic factors, or disease. The structural complexity and disease-relevance of mitochondria have stimulated efforts to generate image analysis tools for describing mitochondrial morphology for therapeutic development. Using high-content analysis, we measured multiple morphological parameters and employed unbiased feature clustering to identify the most robust pair of texture metrics that described mitochondrial state. Here, we introduce a novel image analysis pipeline to enable rapid and accurate profiling of mitochondrial morphology in various cell types and pharmacological perturbations. We applied a high-content adapted implementation of our tool, MitoProfilerHC, to quantify mitochondrial morphology changes in i) a mammalian cell dose response study and ii) compartment-specific drug effects in primary neurons. Next, we expanded the usability of our pipeline by using napari, a Python-powered image analysis tool, to build an open-source version of MitoProfiler and validated its performance and applicability. In conclusion, we introduce MitoProfiler as both a high-content-based and an open-source method to accurately quantify mitochondrial morphology in cells, which we anticipate to greatly facilitate mechanistic discoveries in mitochondrial biology and disease.

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Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models

Chin,

Joy,

Samaddar

et al. 2024

Preprint

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Context-Specific Stress Causes Compartmentalized SARM1 Activation and Local Degeneration in Cortical Neurons

Hinz,

Villegas,

Roberts

et al. 2024

J. Neurosci.

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SARM1 is an inducible NADase that localizes to mitochondria throughout neurons and senses metabolic changes that occur after injury. Minimal proteomic changes are observed upon either SARM1 depletion or activation, suggesting that SARM1 does not exert broad effects on neuronal protein homeostasis. However, whether SARM1 activation occurs throughout the neuron in response to injury and cell stress remains largely unknown. Using a semi-automated imaging pipeline and a custom-built deep learning scoring algorithm, we studied degeneration in both mixed sex mouse primary cortical neurons and male human iPSC derived cortical neurons in response to a number of different stressors. We show that SARM1 activation is differentially restricted to specific neuronal compartments depending on the stressor. Cortical neurons undergo SARM1-dependent axon degeneration after mechanical transection and SARM1 activation is limited to the axonal compartment distal of the injury site. However, global SARM1 activation following vacor treatment causes both cell body and axon degeneration. Context-specific stressors, such as microtubule dysfunction and mitochondrial stress, induce axonal SARM1 activation leading to SARM1-dependent axon degeneration and SARM1-independent cell body death. Our data reveal that compartment-specific SARM1-mediated death signaling is dependent on the type of injury and cellular stressor.Significance StatementSARM1 is an important regulator of active axon degeneration after injury in the peripheral nervous system. Here we show that SARM1 can also be activated by a number of different cellular stressors in cortical neurons of the central nervous system. Loss or activation of SARM1 does not cause large scale changes in global protein homeostasis. However, context-dependent SARM1 activation is localized to specific neuronal compartments and results in localized degeneration of axons. Understanding which cell stress pathways are responsible for driving degeneration of distinct neuronal compartments under what cellular stress conditions and in which neuronal subtypes, will inform development of neurodegenerative disease therapeutics.

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SARM1 is responsible for calpain-dependent dendrite degeneration in mouse hippocampal neurons

Cited by 2 publications

References 65 publications

Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models

Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models

Context-Specific Stress Causes Compartmentalized SARM1 Activation and Local Degeneration in Cortical Neurons

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