Biology subjects

Tuxworth, R. I.

Publications and source records attributed to Tuxworth, R. I..

3 recordsLinked to original sources

bioRxiv2024

The fine-tuning of synapse development by oxidative stress and autophagy requires presynaptic ATM kinase

Two processes held in delicate balance during the fine tuning of synapse development are oxidative stress and autophagy: each can promote synapse expansion yet in excess are toxic. How this balance is maintained is not fully understood. While ataxia-telangiectasia mutated (ATM) is recognized as a key regulator of the DNA damage response, there is increasing evidence of a neuronal-specific role for this ubiquitous kinase and deficiency causes early-onset neurodegeneration. We report a requirement for presynaptic Drosophila ATM (dATM) in neurodevelopment that is independent of its functions in the DNA damage response. Reduction of presynaptic dATM expression causes hypersensitivity to raised oxidative stress and a failure to induce autophagy which leaves mitochondria in excess in neurons. We demonstrate that presynaptic dATM coordinates autophagy through the conserved ATM-AMPK axis. Similarly to mammalian ATM, neuronal dATM is predominantly cytosolic and forms synaptic foci. dATM also colocalizes with autophagosomes. We propose a model wherein dATM responds to increased reactive oxygen species resulting from heightened neuronal activity by activating autophagy to induce synaptic growth, while protecting the neuron from excitotoxicity and oxidative stress.

developmental biology↗

bioRxiv2018

Attenuating the DNA damage response to double strand breaks is neuroprotective

DNA double-strand breaks are a feature of many acute and long-term neurological disorders, including neurodegeneration, following neurotrauma and after stroke. Persistent activation of the DNA damage response in response to double strand breaks contributes to neural dysfunction and pathology as it can force post-mitotic neurons to re-enter the cell cycle leading to senescence or apoptosis. Mature, non-dividing neurons may tolerate low levels of DNA damage, in which case muting the DNA damage response might be neuroprotective. Here, we show that attenuating the DNA damage response by targeting the meiotic recombination 11, Rad50, Nijmegen breakage syndrome 1 complex, which is involved in double strand break recognition, is neuroprotective in three neurodegeneration models in Drosophila and prevents A{beta}1-42-induced loss of synapses in embryonic hippocampal neurons. Attenuating the DNA damage response after optic nerve injury is also neuroprotective to retinal ganglion cells and promotes dramatic regeneration of their neurites both in vitro and in vivo. Dorsal root ganglion neurons similarly regenerate when the DNA damage response is targeted in vitro and in vivo and this strategy also induces significant restoration of lost function after spinal cord injury. We conclude that muting the DNA damage response in the nervous system is neuroprotective in multiple neurological disorders. Our results point to new therapies to maintain or repair the nervous system.

neuroscience↗

bioRxiv2018

The neuronal ceroid lipofuscinosis protein, Cln7, regulates neural development from the post-synaptic cell.

The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Using the Drosophila larval neuromuscular junction as a model to study neural development, we demonstrate that Cln7 is required for the normal growth of synapses. In a Cln7 mutant, synapses fail to develop fully leading to reduced function and behavioral changes with dysregulation of TOR activity. Cln7 expression is restricted to the post-synaptic cell and the protein localizes to vesicles immediately adjacent to the post-synaptic membrane. Our data suggest an involvement for Cln7 in regulating trans-synaptic communication.

developmental biology↗