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Brody, E. M.

Publications and source records attributed to Brody, E. M..

2 recordsLinked to original sources
bioRxiv2022

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME is expressed by both mouse and human neurons. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. The frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME deficiency prolonged survival, ameliorated motor dysfunction, and rescued motor neuron loss in the SOD1G93A mouse model of ALS. GSDME knockdown also protected against neurite loss in ALS patient iPSC-derived motor neurons. Thus, we identify GSDME as an executioner of neuronal mitochondrial dysfunction that contributes to neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/513927v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@113c13dorg.highwire.dtl.DTLVardef@1f3c5caorg.highwire.dtl.DTLVardef@13e75adorg.highwire.dtl.DTLVardef@19fdc93_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGSDME is expressed by neurons and activated by mitochondrial neurotoxins C_LIO_LIActivated GSDME drives axonal mitochondrial damage and neurite loss prior to cell death C_LIO_LIALS/FTD associated TDP-43 and PR-50 induces GSDME-driven neurite loss in mouse and human iPSC-derived neurons. C_LIO_LISOD1G93A mice show ameliorated disease progression and motor neuron loss in absence of GSDME C_LI

neuroscience↗
bioRxiv2022

The Adaptor Protein 2 (AP2) complex modulates habituation and behavioral selection across multiple pathways and time windows

Animals constantly perceive and integrate information across sensory modalities, and their nervous systems must select behavioral responses appropriate to the current situation and prior experience. Genetic factors supporting this behavioral flexibility are often disrupted in neuropsychiatric conditions, and our previous work revealed the disease-associated ap2s1 gene critically supports habituation learning in acoustically-evoked escape behavior of zebrafish. ap2s1 encodes a subunit of the AP2 endocytosis adaptor complex and has been linked to autism spectrum disorder, though its mechanism and direct behavioral importance have not been established. Here, we show that multiple subunits of the AP2 complex regulate acoustically-evoked behavior selection and habituation learning. Furthermore, ap2s1 biases the choice between distinct escape behaviors in sensory modality-specific manners, and more broadly regulates action selection across different sensory contexts. Using tissue-specific and inducible transgenic rescue, we demonstrate that the AP2 complex functions acutely and in the nervous system to modulate acoustically-evoked habituation learning, suggesting several spatially and/or temporally distinct mechanisms through which AP2 regulates different aspects of escape behavior selection and performance. Altogether, we demonstrate that the AP2 complex coordinates action selection across stimulus modalities and contexts, providing a new vertebrate model for the role of ap2s1 in human conditions including autism spectrum disorder. SIGNIFICANCE STATEMENTThe AP2S1 gene has been linked to learning disabilities and autism spectrum disorders (ASD), though the mechanisms underlying its impact on human behavior are unknown. We explored how, when, and where this gene regulates vertebrate behavior, developing a zebrafish model to identify the roles and mechanisms through which ap2s1 modulates behavior. We find that ap2s1 regulates simple acoustically-evoked learning, as well as how individuals bias behavioral choice in a wide variety of contexts. We show that ap2s1 acts at multiple distinct time periods and locations both within and outside of neuronal tissues, revealing the diverse mechanisms and pathways through which it modulates vertebrate behavior.

neuroscience↗