Histopathological changes of the spinal cord and motor neuron dynamics in SOD1 Tg mice.

We analyzed the histopathological changes and the number of motor neurons (MNs) in the lumbar spinal cord of Cu/Zn superoxide dismutase transgenic (SOD1Tg) mice, which are frequently used as a disease model of amyotrophic lateral sclerosis (ALS). In SOD1Tg mice, hyaline inclusions and foamy vacuoles in the neuronal cell body were observed at 7 weeks of age before neurologic symptoms, and large vacuoles, spheroid formation, and nerve cell aggregation became prominent after 13 weeks of age. The number of healthy MNs was 28.

ASK1 promotes uterine inflammation leading to pathological preterm birth.

It is widely accepted that enhanced uterine inflammation associated with microbial infection is a main causative factor for preterm birth. However, little is known about the molecular basis by which inflammation is associated with preterm birth. Here, we demonstrate that apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein 3-kinase family, facilitates inflammation-induced preterm birth and that inhibition of ASK1 activity is sufficient to suppress preterm birth.

Genome-wide siRNA screening reveals that DCAF4-mediated ubiquitination of optineurin stimulates autophagic degradation of Cu,Zn-superoxide dismutase.

() is one of the genes implicated in the devastating neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Although the precise mechanisms of mutant (SOD1)-induced motoneuron toxicity are still unclear, defects in SOD1 proteostasis are known to have a critical role in ALS pathogenesis. We previously reported that the SOD1 adopts a conformation that exposes a Derlin-1-binding region (DBR) and that DBR-exposed SOD1 interacts with Derlin-1, leading to motoneuron death.

A small-molecule inhibitor of SOD1-Derlin-1 interaction ameliorates pathology in an ALS mouse model.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder. Despite its severity, there are no effective treatments because of the complexity of its pathogenesis. As one of the underlying mechanisms of Cu, Zn superoxide dismutase (SOD1) gene mutation-induced ALS, SOD1 mutants (SOD1) commonly interact with an endoplasmic reticulum-resident membrane protein Derlin-1, triggering motoneuron death.

The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 ().

[Zinc depletion and ER stress].

Zinc is required for the proper functions of proteins and cell signaling. Because the perturbation of zinc homeostasis causes various human diseases, cells need to regulate cellular zinc homeostasis strictly. However, the mechanisms by which cells respond to zinc deficiency and restore cellular homeostasis are largely unknown.

The ASK1-specific inhibitors K811 and K812 prolong survival in a mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with no cure. To develop effective treatments for this devastating disease, an appropriate strategy for targeting the molecule responsible for the pathogenesis of ALS is needed. We previously reported that mutant SOD1 protein causes motor neuron death through activation of ASK1, a mitogen-activated protein kinase kinase kinase.

SOD1 in neurotoxicity and its controversial roles in SOD1 mutation-negative ALS.

Amyotrophic lateral sclerosis (ALS) is a serious neurodegenerative disorder that is characterized by the selective death of motor neurons. While the fundamental cause of the disorder is still unclear, the first identified risk gene, Cu,Zn superoxide dismutase (SOD1), has led to the proposal of several mechanisms that are relevant to its pathogenesis. These include excitotoxicity, oxidative stress, ER stress, mitochondrial dysfunction, axonal transport disruption, prion-like propagation, and non-cell autonomous toxicity of neuroglia.

A systematic immunoprecipitation approach reinforces the concept of common conformational alterations in amyotrophic lateral sclerosis-linked SOD1 mutants.

Mutations in the Cu, Zn superoxide dismutase (SOD1) gene are one of the causative agents of amyotrophic lateral sclerosis (ALS). Although more than 100 different mutations in SOD1 have been identified, it is unclear whether all the mutations are pathogenic or just single nucleotide polymorphisms (SNPs) unrelated to the disease. Our previous systematic analysis found that all pathogenic SOD1 mutants (SOD1(mut)) have a common property, namely, an association with Derlin-1, a component of the endoplasmic reticulum-associated degradation machinery.

SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency.

Zinc is an essential trace element, and impaired zinc homeostasis is implicated in the pathogenesis of various human diseases. However, the mechanisms cells use to respond to zinc deficiency are poorly understood. We previously reported that amyotrophic lateral sclerosis (ALS)-linked pathogenic mutants of SOD1 cause chronic endoplasmic reticulum (ER) stress through specific interactions with Derlin-1, which is a component of the ER-associated degradation machinery.

A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.

Objective: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by the selective loss of upper and lower motoneurons. Although >100 different Cu, Zn superoxide dismutase (SOD1) mutations have been identified in ALS patients, it remains controversial whether all of them are disease-causative mutations. Therefore, it is necessary to develop molecular mechanism-based diagnosis and treatment of ALS caused by SOD1 mutations.

Ubiquitin-like sequence in ASK1 plays critical roles in the recognition and stabilization by USP9X and oxidative stress-induced cell death.

Ubiquitination is an important posttranslational modification that regulates various cellular processes, including signal transduction. However, physiological roles of ubiquitination in the regulation of MAPK pathways are poorly understood. Here, we identified the deubiquitinating enzyme USP9X as a binding partner of ASK1 that mediates oxidative stress-induced cell death through activation of the JNK and p38 MAPK pathways.

Targeting ASK1 in ER stress-related neurodegenerative diseases.

The accumulation of malfolded proteins in the endoplasmic reticulum (ER) induces ER stress, leading to the disturbance of ER function. To restore ER function and ER homeostasis, cells possess a highly specific ER quality control system termed the unfolded protein response (UPR), which increases the capacity of protein folding and reduces the amount of malfolded proteins. In case of prolonged ER stress or malfunction of the UPR, apoptosis signaling is activated.