Real-time visualization of oxidative stress-mediated neurodegeneration of individual spinal motor neurons in vivo

Abstract

Generation of reactive oxygen species (ROS) has been shown to be important for many physiological processes, ranging from cell differentiation to apoptosis. With the development of the genetically encoded photosensitiser KillerRed (KR) it is now possible to efficiently produce ROS dose-dependently in a specific cell type upon green light illumination. Zebrafish are the ideal vertebrate animal model for these optogenetic methods because of their transparency and efficient transgenesis. Here we describe a zebrafish model that expresses membrane-targeted KR selectively in motor neurons. We show that KR-activated neurons in the spinal cord undergo stress and cell death after induction of ROS. Using single-cell resolution and time-lapse confocal imaging, we selectively induced neurodegeneration in KR-expressing neurons leading to characteristic signs of apoptosis and cell death. We furthermore illustrate a targeted microglia response to the induction site as part of a physiological response within the zebrafish spinal cord. Our data demonstrate the successful implementation of KR mediated ROS toxicity in motor neurons in vivo and has important implications for studying the effects of ROS in a variety of conditions within the central nervous system, including aging and age-related neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Human iPSC-derived astrocytes from ALS patients with mutated C9ORF72 show increased oxidative stress and neurotoxicity

“…For instance, conditioned media derived from mouse astrocytes expressing mutated SOD1 or TDP43, has led to rapid oxidative stress and extensive spinal MN-specific death within a few days [50]. Moreover, oxidative stress induced by a genetic approach specifically in spinal motor neurons in live zebrafish resulted in motor neuron cell death [51]. Thus, it is plausible that reduced protection against oxidative stress by C9-mutated astrocytes, contributes to the gradual loss of motor neurons with age and the eventual onset of the signs and symptoms of fALS.…”

Modulation of Adenosine Receptors and Antioxidative Effect of Beer Extracts in in Vitro Models

“…A moderate consumption of certain low-alcohol beverages, as wine and beer, could have beneficial properties for our health, showing a protective effect even on AD [47,48,49]. Oxidative stress is involved in neurodegenerative pathologies [50,51,52] and could be fought by the antioxidant ability of beer [5]. Our results show the different effects of beers (dark, non-alcoholic, and lager) in cells (C6 and SH-SY5Y) and the protection by these beers’ extracts against oxidative stress.…”

Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

“…The CNS is especially susceptible to oxidative damage (Cordeiro, 2014). The brain is largely formed by PUFAs with high sensitivity to lipid peroxidation (Nunomura et al, 2006), motor neurons are highly sensitive to OS (Simpkins and Dykens, 2008) and the CNS has a poor antioxidant capacity with low activity of protective enzymes such as glutathione peroxidase (GPx), catalase (CAT) or superoxide dismutase (SOD) and poor capacity for cell regeneration (Fischer and Maier, 2015;Kim et al, 2015;Formella et al, 2018). Although the brain only accounts for 2% of body weight (Mergenthaler et al, 2013) and mitochondrial density is higher in myocytes than in neuronal cells (Gandhi and Abramov, 2012), it is an organ with a high metabolic rate that can consume up to 20% of the total oxygen of the body (Moreira et al, 2009;Ronnett et al, 2009).…”