A. Calvo : A focus on amyotrophic lateral sclerosis 🗓 🗺

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Amyotrophic Lateral Sclerosis (ALS) belongs to the group of motor neuron diseases, involving the loss of cortex, brainstem, and spinal cord motor neurons that result in muscle paralysis [1]. Motor neurons, which are localized in the brain, brainstem and spinal cord, behave as a crucial links between the nervous system and the voluntary muscles of the body, as they let synaptic signals travel from upper motor neurons in the brain to lower motor neurons in the spinal cord and finally to muscles. In accordance with the Awaji criteria [1], both the upper motor neurons and the lower motor neurons degenerate or die in ALS, and as a consequence the communication between neuron and muscle is lost, prompting the progressive muscle weakening and the appearance of fasciculations. In the later stages of the disease, patients become paralyzed although the disease usually does not impair a person’s mind or intelligence. The majority of ALS cases are sporadic and 5-10% of cases correspond to familial cases linked to a genetic mutation in the most common genes related to the disease [2].



Up to now the most known mutations that produce the typical adult onset ALS phenotype are related to the copper/zinc superoxide-dismutase-1 gene (SOD1), Tar DNA-binding protein gene (TARDBP) (previously known as TDP-43), DNA/RNA-binding protein called FUS (fused in sarcoma), TLS (translocation in liposarcoma), and the most recent hexanucleotide repeat expansion in C9ORF72 [3,4]. The proteins encoded by these genes have been found in aggregated deposits within diseased tissue albeit the exact mechanisms that drive and cause disease progression still remain unknown. Mutations in SOD1 are the second most common cause of familial ALS. Currently there is no generally accepted hypothesis as to how these mutations drive disease, but it does appear to be the gain of a toxic function and not the loss of SOD1 activity [5]. SOD enzyme catalyzes the production of O2 and H2O2 from superoxide (O2−), protecting the cell from the harmful effects of superoxide. Since oxidative damage characterizes ALS, considerable effort has explored the role of copper in ALS pathogenesis caused by mutant ALS. In this sense, transgenic mice carrying the SOD1G93A mutant will be analyze to explore the molecular effect of this mutation in this murine model of ALS. More in depth, the search of biomakers and the translational study from the animal model to human samples performed in the LAGENBIO group will be explain in detail.



[1] BR Brooks, RG Miller, M Swash, et al. Amyotroph Lateral Scler Other Motor Neuron Disord., 2000, 1, 293-299.

[2] P Pasinelli, RH Brown. Nat Rev Neurosci., 2006, 7, 710-723.

[3] PM Andersen, A Al-Chalabi. Nat Rev Neurol., 2011, 7, 603-615.

[4] Z Xhu, M Poidevin, X Li, et al. Proc Natl Acad Sci. USA, 2013, 110, 7778-7783.

[5] SJ Kaur, SR McKeown, S Rashid. Gene, 2016, 577, 109-118.



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