Lee JK, Shin JH, Hwang SG, Gwag BJ, McKee AC, Lee J, Kowall NW, Ryu H, Lim DS, Choi EJ. MST1 functions as a key modulator of neurodegeneration in a mouse model of ALS. Proc Natl Acad Sci U S A. 2013 Jul 16;110(29):12066-71. PubMed.
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Using cellular and animal models, Lee and co-workers demonstrate that the activation of the multifunctional serine-threonine kinase MST1 (Mammalian sterile 20 (STE20)-like kinase 1) may be responsible for oxidative stress-mediated cell death specifically in motor neurons during ALS pathology. The process of apoptosis is vital during normal brain development, however in the mature brain, abnormal neuronal death is a hallmark of many neurodegenerative diseases, and as such is observed in ALS.
Previously, MST1 was implicated in controlling cell death triggered by oxidative stress. Here, the authors provide a mechanism by which oxidative damage caused by mutant SOD1 leads to selective neuronal death. They found that MST1 was activated by phosphorylation in motor neurons and not in astrocytes in the lumbar spinal cord of an ALS mouse model overexpressing the G93A SOD1 mutant. Moreover, when they deleted MST1 the ALS phenotype of SOD1G93A mice was significantly delayed, and the animals had improved motor neuron viability, clearly highlighting the role of MST1 in the loss of motor neurons during disease progression. Interestingly, the authors found that thioredoxin1 (Trx1) associates with MST1 and that this interaction is critical for the viability of motor neurons, since mutant SOD1 induces dissociation of MST1 and Trx1 and leads to homo-dimerization of the former, ultimately resulting in the activation of the apoptosis pathway.
Defects in autophagic flux are generally regarded as a feature of ALS pathology. Of note, the deletion of MST1 also rescued defects in autophagic flux in the spinal cord when SOD1G93A was expressed.
In summary, we highly recommend this insightful paper, since it highlights a connection between many molecular and cellular aspects of the disease, implicating Trx1 and MST1 as master regulators of neuronal cell death and thereby identifying them as potential therapeutic targets.
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