Deletion of Ripk3 Prevents Motor Neuron Death In Vitro but not In Vivo

Oligodendrocytes have recently been implicated in the pathophysiology of amyotrophic lateral sclerosis (ALS). Here we show that, in vitro, mutant superoxide dismutase 1 (SOD1) mouse oligodendrocytes induce WT motor neuron (MN) hyperexcitability and death. Moreover, we efficiently derived human oligodendrocytes from a large number of controls and patients with sporadic and familial ALS, using two different reprogramming methods. All ALS oligodendrocyte lines induced MN death through conditioned medium (CM) and in coculture. CM-mediated MN death was associated with decreased lactate production and release, whereas toxicity in coculture was lactate-independent, demonstrating that MN survival is mediated not only by soluble factors. Remarkably, human SOD1 shRNA treatment resulted in MN rescue in both mouse and human cultures when knockdown was achieved in progenitor cells, whereas it was ineffective in differentiated oligodendrocytes. In fact, early SOD1 knockdown rescued lactate impairment and cell toxicity in all lines tested, with the exclusion of samples carrying chromosome 9 ORF 72 (C9orf72) repeat expansions. These did not respond to SOD1 knockdown nor did they show lactate release impairment. Our data indicate that SOD1 is directly or indirectly involved in ALS oligodendrocyte pathology and suggest that in this cell type, some damage might be irreversible. In addition, we demonstrate that patients with C9ORF72 represent an independent patient group that might not respond to the same treatment.

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ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1810413115 ◽

2018 ◽

Vol 115 (51) ◽

pp. E11904-E11913 ◽

Cited By ~ 48

Author(s):

Marisa Kamelgarn ◽

Jing Chen ◽

Lisha Kuang ◽

Huan Jin ◽

Edward J. Kasarskis ◽

...

Keyword(s):

Motor Neuron ◽

Protein Biosynthesis ◽

Protein Composition ◽

Protein Translation ◽

Fibroblast Cells ◽

Neuron Death ◽

Nonsense Mediated Decay ◽

Cytoplasmic Granules ◽

Motor Neuron Death

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by preferential motor neuron death. Approximately 15% of ALS cases are familial, and mutations in the fused in sarcoma (FUS) gene contribute to a subset of familial ALS cases. FUS is a multifunctional protein participating in many RNA metabolism pathways. ALS-linked mutations cause a liquid–liquid phase separation of FUS protein in vitro, inducing the formation of cytoplasmic granules and inclusions. However, it remains elusive what other proteins are sequestered into the inclusions and how such a process leads to neuronal dysfunction and degeneration. In this study, we developed a protocol to isolate the dynamic mutant FUS-positive cytoplasmic granules. Proteomic identification of the protein composition and subsequent pathway analysis led us to hypothesize that mutant FUS can interfere with protein translation. We demonstrated that the ALS mutations in FUS indeed suppressed protein translation in N2a cells expressing mutant FUS and fibroblast cells derived from FUS ALS cases. In addition, the nonsense-mediated decay (NMD) pathway, which is closely related to protein translation, was altered by mutant FUS. Specifically, NMD-promoting factors UPF1 and UPF3b increased, whereas a negative NMD regulator, UPF3a, decreased, leading to the disruption of NMD autoregulation and the hyperactivation of NMD. Alterations in NMD factors and elevated activity were also observed in the fibroblast cells of FUS ALS cases. We conclude that mutant FUS suppresses protein biosynthesis and disrupts NMD regulation, both of which likely contribute to motor neuron death.

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AMPA receptor activation, but not the accumulation of endogenous extracellular glutamate, induces paralysis and motor neuron death in rat spinal cord in vivo

Journal of Neurochemistry ◽

10.1111/j.1471-4159.2004.02383.x ◽

2004 ◽

Vol 89 (4) ◽

pp. 988-997 ◽

Cited By ~ 39

Author(s):

Juan Carlos Corona ◽

Ricardo Tapia

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Ampa Receptor ◽

Receptor Activation ◽

Rat Spinal Cord ◽

Neuron Death ◽

Extracellular Glutamate ◽

Motor Neuron Death

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Methylcobalamin prevents mutant superoxide dismutase-1-induced motor neuron death in vitro

Neuroreport ◽

10.1097/wnr.0000000000000716 ◽

2017 ◽

Vol 28 (2) ◽

pp. 101-107 ◽

Cited By ~ 6

Author(s):

Shunsuke Ito ◽

Yukina Izumi ◽

Tetsuhiro Niidome ◽

Yuichi Ono

Keyword(s):

Superoxide Dismutase ◽

Motor Neuron ◽

Superoxide Dismutase 1 ◽

Neuron Death ◽

Motor Neuron Death

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Activated microglia (BV-2) facilitation of TNF-α-mediated motor neuron death in vitro

Journal of Neuroimmunology ◽

10.1016/s0165-5728(02)00141-8 ◽

2002 ◽

Vol 128 (1-2) ◽

pp. 31-38 ◽

Cited By ~ 64

Author(s):

Bei Ping He ◽

Weiyan Wen ◽

Michael J Strong

Keyword(s):

Motor Neuron ◽

Neuron Death ◽

Activated Microglia ◽

Tnf Α ◽

Motor Neuron Death

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Cellular and molecular mechanisms of motor neuron death in amyotrophic lateral sclerosis

10.3389/978-2-88919-376-9 ◽

2015 ◽

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Molecular Mechanisms ◽

Neuron Death ◽

Motor Neuron Death ◽

Lateral Sclerosis

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Simvastatin Prevents Neurodegeneration in the MPTP Mouse Model of Parkinson’s Disease via Inhibition of A1 Reactive Astrocytes

NeuroImmunoModulation ◽

10.1159/000513678 ◽

2021 ◽

pp. 1-8

Author(s):

Ren-Wei Du ◽

Wen-Guang Bu

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Underlying Mechanism ◽

Reactive Astrocytes ◽

Dopamine Neurons ◽

Neuron Death ◽

Neurologic Disorders

Emerging evidence indicates that A1 reactive astrocytes play crucial roles in the pathogenesis of Parkinson’s disease (PD). Thus, development of agents that could inhibit the formation of A1 reactive astrocytes could be used to treat PD. Simvastatin has been touted as a potential neuroprotective agent for neurologic disorders such as PD, but the specific underlying mechanism remains unclear. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and primary astrocytes/neurons were prepared to investigate the effects of simvastatin on PD and its underlying mechanisms in vitro and in vivo. We show that simvastatin protects against the loss of dopamine neurons and behavioral deficits in the MPTP mouse model of PD. We also found that simvastatin suppressed the expression of A1 astrocytic specific markers in vivo and in vitro. In addition, simvastatin alleviated neuron death induced by A1 astrocytes. Our findings reveal that simvastatin is neuroprotective via the prevention of conversion of astrocytes to an A1 neurotoxic phenotype. In light of simvastatin favorable properties, it should be evaluated in the treatment of PD and related neurologic disorders characterized by A1 reactive astrocytes.

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Bixafen, a succinate dehydrogenase inhibitor fungicide, causes microcephaly and motor neuron axon defects during development

10.1101/2020.08.15.252254 ◽

2020 ◽

Author(s):

Alexandre Brenet ◽

Rahma Hassan-Abdi ◽

Nadia Soussi-Yanicostas

Keyword(s):

Motor Neuron ◽

Succinate Dehydrogenase ◽

Toxicity Testing ◽

Mitochondrial Respiratory Chain ◽

Modern Agriculture ◽

Transgenic Lines ◽

Vertebrate Model ◽

The Central Nervous System

AbstractSuccinate dehydrogenase inhibitors (SDHIs), the most widely used fungicides in agriculture today, act by blocking succinate dehydrogenase (SDH), an essential and evolutionarily conserved component of mitochondrial respiratory chain. Recent results showed that several SDHIs used as fungicides not only inhibit the SDH activity of target fungi but also block this activity in human cells in in vitro models, revealing a lack of specificity and thus a possible health risk for exposed organisms, including humans. Despite the frequent detection of SDHIs in the environment and on harvested products and their increasing use in modern agriculture, their potential toxic effects in vivo, especially on neurodevelopment, are still under-evaluated. Here we assessed the neurotoxicity of bixafen, one of the latest-generation SDHIs, which had never been tested during neurodevelopment. For this purpose, we used a well-known vertebrate model for toxicity testing, namely zebrafish transparent embryos, and live imaging using transgenic lines labelling the brain and spinal cord. Here we show that bixafen causes microcephaly and defects on motor neuron axon outgrowth and their branching during development. Our findings show that the central nervous system is highly sensitive to bixafen, thus demonstrating in vivo that bixafen is neurotoxic in vertebrates and causes neurodevelopmental defects. This work adds to our knowledge of the toxic effect of SDHIs on neurodevelopment and may help us take appropriate precautions to ensure protection against the neurotoxicity of these substances.

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