Biology subjects

Nebiyou, M.

Publications and source records attributed to Nebiyou, M..

3 recordsLinked to original sources

bioRxiv2023

ATF2 phosphorylation is a key event in neuronal apoptosis, linking the DLK/LZK kinase cascade to JUN upregulation

Apoptotic neuron death is a key feature of neurodegenerative disease. Considerable efforts have been made to target this pathway but the molecular mechanisms remain incompletely understood. Here, we conducted an unbiased whole genome CRISPR inhibition screen in human neurons to discover genes required for their death and identified known targets including the kinase MAP3K12 (DLK) and the transcription factor JUN. In addition, this screen revealed a potential role for the transcription factor ATF2. We demonstrate that ATF2 phosphorylation by MAP3 kinases is the core driver of the pro-apoptotic transcriptional response. Surprisingly, JUN phosphorylation is not required for apoptosis. However, the phosphorylation of ATF2 and upregulation of JUN expression are crucial. ATF2 therefore converts the kinase signal into a transcriptional response. Inhibiting ATF2 in cultured human neurons prevents cell death. Notably we show that ATF2 knockdown is neuroprotective in injury models in vivo. Thus, ATF2 provides a promising new target for a wide range of neurodegenerative disorders.

neuroscience↗

bioRxiv2023

DLK-dependent mitochondrial fission drives axon degeneration and neuronal cell death

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we developed a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrated that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We found that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a new mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protected mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a powerful platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and new focus for therapeutic intervention.

neuroscience↗

bioRxiv2022

Local production of reactive oxygen species drives vincristine-induced axon degeneration

Neurological side effects arising from chemotherapy, such as severe pain and cognitive impairment, are a major concern for cancer patients. These major side effects can lead to reduction or termination of chemotherapy medication in patients, negatively impacting their prognoses. With cancer survival rates improving dramatically, addressing side effects of cancer treatment has become pressing. Here, we use iPSC-derived human neurons to investigate the molecular mechanisms that lead to neurotoxicity induced by vincristine, a common chemotherapeutic used to treat solid tumors. Our results uncover a novel mechanism by which vincristine causes a local increase in mitochondrial proteins that produce reactive oxygen species (ROS) in the axon. Vincristine triggers a cascade of axon pathology, causing mitochondrial dysfunction that leads to elevated axonal ROS levels and SARM1-dependent axon degeneration. Importantly, we show that the neurotoxic effect of increased axonal ROS can be mitigated by the small molecule mdivi-1 and antioxidants glutathione and mitoquinone, identifying a novel therapeutic avenue to treat the neurological effects of chemotherapy.

neuroscience↗