Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS

Wang, Taide; Perera, Nirma D.; Chiam, Mathew D. F.; Cuic, Brittany; Wanniarachchillage, Nayomi; Tomas, Doris; Samson, André L.; Cawthorne, Wayne; Valor, Eric N.; Murphy, James M.; Turner, Bradley J.

doi:10.1038/s41418-019-0457-8

Cited by 64 publications

(58 citation statements)

References 42 publications

(81 reference statements)

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“…A role for necroptosis signalling in ALS has also been proposed as pharmacological inhibition or genetic ablation of RIPK1 delayed symptom onset in the SOD1 G93A mouse model [ 144 ]. However, subsequent studies have questioned the role of necroptosis in ALS as neither a kinase dead mutant of RIPK1 [ 145 ], nor deletion of MLKL [ 146 ], delayed disease progression in the same mouse model.…”

Section: Ubiquitin Signalling In Neuronal Cell Deathmentioning

confidence: 99%

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

et al. 2021

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Neurodegenerative diseases are characterised by progressive damage to the nervous system including the selective loss of vulnerable populations of neurons leading to motor symptoms and cognitive decline. Despite millions of people being affected worldwide, there are still no drugs that block the neurodegenerative process to stop or slow disease progression. Neuronal death in these diseases is often linked to the misfolded proteins that aggregate within the brain (proteinopathies) as a result of disease-related gene mutations or abnormal protein homoeostasis. There are two major degradation pathways to rid a cell of unwanted or misfolded proteins to prevent their accumulation and to maintain the health of a cell: the ubiquitin–proteasome system and the autophagy–lysosomal pathway. Both of these degradative pathways depend on the modification of targets with ubiquitin. Aging is the primary risk factor of most neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. With aging there is a general reduction in proteasomal degradation and autophagy, and a consequent increase of potentially neurotoxic protein aggregates of β-amyloid, tau, α-synuclein, SOD1 and TDP-43. An often over-looked yet major component of these aggregates is ubiquitin, implicating these protein aggregates as either an adaptive response to toxic misfolded proteins or as evidence of dysregulated ubiquitin-mediated degradation driving toxic aggregation. In addition, non-degradative ubiquitin signalling is critical for homoeostatic mechanisms fundamental for neuronal function and survival, including mitochondrial homoeostasis, receptor trafficking and DNA damage responses, whilst also playing a role in inflammatory processes. This review will discuss the current understanding of the role of ubiquitin-dependent processes in the progressive loss of neurons and the emergence of ubiquitin signalling as a target for the development of much needed new drugs to treat neurodegenerative disease.

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Section: Ubiquitin Signalling In Neuronal Cell Deathmentioning

confidence: 99%

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

et al. 2021

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“…[55,56]). Consequently, errant necroptosis has been implicated in the pathology of inflammatory syndromes [57], atherosclerosis [58], cardiac [59] and kidney [60] ischemia/reperfusion injury, sepsis [61][62][63], inflammatory bowel disease [64], neurodegenerative diseases [65], and cancer [66], although some of these attributions remain the matter of debate [62,[67][68][69][70][71][72]. In addition, damage caused by some bacterial infections have been proposed to be attributable to excessive necroptosis and inflammation [73,74].…”

Section: Therapeutic Targeting Of Necroptosis In Human Diseasementioning

confidence: 99%

The regulation of necroptosis by post-translational modifications

et al. 2021

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Necroptosis is a caspase-independent, lytic form of programmed cell death whose errant activation has been widely implicated in many pathologies. The pathway relies on the assembly of the apical protein kinases, RIPK1 and RIPK3, into a high molecular weight cytoplasmic complex, termed the necrosome, downstream of death receptor or pathogen detector ligation. The necrosome serves as a platform for RIPK3-mediated phosphorylation of the terminal effector, the MLKL pseudokinase, which induces its oligomerization, translocation to, and perturbation of, the plasma membrane to cause cell death. Over the past 10 years, knowledge of the post-translational modifications that govern RIPK1, RIPK3 and MLKL conformation, activity, interactions, stability and localization has rapidly expanded. Here, we review current knowledge of the functions of phosphorylation, ubiquitylation, GlcNAcylation, proteolytic cleavage, and disulfide bonding in regulating necroptotic signaling. Post-translational modifications serve a broad array of functions in modulating RIPK1 engagement in, or exclusion from, cell death signaling, whereas the bulk of identified RIPK3 and MLKL modifications promote their necroptotic functions. An enhanced understanding of the modifying enzymes that tune RIPK1, RIPK3, and MLKL necroptotic functions will prove valuable in efforts to therapeutically modulate necroptosis. Facts • Post-translational modifications of the RIPK1 and RIPK3 kinases and MLKL pseudokinase regulate their localization, activity, conformation, oligomerization, and protein interactions • To date, principally activating modifications have been reported for RIPK3 and MLKL How do RIPK3 and MLKL modifications control their protein interactions and prompt cell death?

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“…The role of necroptosis in ALS remains controversial, as motor neuron disease in murine models is independent of necroptosis signaling and MLKL activation [99,100]. In contrast, recent in vitro work using a fully-humanized co-culture system demonstrated that an unidentified toxic factor secreted from primary astrocytes from sporadic ALS, but not those from control patients, triggered necroptosis-mediated death of motor neurons [69].…”

Section: Discussionmentioning

confidence: 99%

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

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Gurm

Turnbull

et al. 2020

Cells

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Motor neuron degeneration and spinal cord demyelination are hallmark pathological events in Amyotrophic Lateral Sclerosis (ALS). Endogenous retrovirus-K (ERVK) expression has an established association with ALS neuropathology, with murine modeling pointing to a role for the ERVK envelope (env) gene in disease processes. Here, we describe a novel viral protein cryptically encoded within the ERVK env transcript, which resembles two distinct cysteine-rich neurotoxic proteins: conotoxin proteins found in marine snails and the Human Immunodeficiency Virus (HIV) Tat protein. Consistent with Nuclear factor-kappa B (NF-κB)-induced retrotransposon expression, the ERVK conotoxin-like protein (CTXLP) is induced by inflammatory signaling. CTXLP is found in the nucleus, impacting innate immune gene expression and NF-κB p65 activity. Using human autopsy specimens from patients with ALS, we further showcase CTXLP expression in degenerating motor cortex and spinal cord tissues, concomitant with inflammation linked pathways, including enhancement of necroptosis marker mixed lineage kinase domain-like (MLKL) protein and oligodendrocyte maturation/myelination inhibitor Nogo-A. These findings identify CTXLP as a novel ERVK protein product, which may act as an effector in ALS neuropathology.

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Necroptosis is dispensable for motor neuron degeneration in a mouse model of ALS

Cited by 64 publications

References 42 publications

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities

The regulation of necroptosis by post-translational modifications

Pro-Inflammatory Signaling Upregulates a Neurotoxic Conotoxin-Like Protein Encrypted Within Human Endogenous Retrovirus-K

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