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Contenuto archiviato il 2024-06-18

Misfolded SOD1 Toxicity in Amyotrophic Lateral Sclerosis

Final Report Summary - MISFOLDED SOD1-ALS (Misfolded SOD1 Toxicity in Amyotrophic Lateral Sclerosis)

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. The reason for the degeneration of motor neurons in ALS is still unknown. Mitochondria have been implicated as a possible target for toxicity by several studies reporting a range of dysfunctions and the toxic binding of misfolded SOD1 to mitochondrial targets. However, the mechanism by which mutant SOD1 associates with mitochondria specifically from affected tissues is still unknown. Preliminary data show that a cytosolic factor in unaffected tissues is responsible for preventing the accumulation of misfolded SOD1. This factor was identified as the macrophage migration inhibitory factor (MIF). MIF inhibits the association of mutant SOD1 with mitochondria and accumulation of misfolded SOD1. The hypothesis of this proposal is that MIF is reduced in abundance or inactive as a chaperone within the CNS, leading to increased accumulation of misfolded SOD1 and neurodegeneration. This proposal aims to unambiguously determine how toxicity is caused by misfolded SOD1 accumulation and finally an attempt to rescue these toxic effects in models of ALS will be done. In Aim 1 of the research we proposed to determine the tissue specificity of misfolded SOD1 accumulation and mitochondrial association and to characterize MIF activity as a chaperone for misfolded SOD1. We have shown that misfolded SOD1 is accumulated specifically within the spinal cord. In a very important finding, we showed that the expression level of MIF is extremely low in the motor neurons comparing to other cell types, suggesting that MIF levels may represent a selective factor for vulnerability of the motor neurons.
These results were published in Neuron (Israelson et al, 2015) and summarized in a mini review
(Abu-Hamad and Israelson, 2015).
In Aim 2 we proposed to determine how mitochondrial association of misfolded SOD1 affects mitochondrial function in the spinal cord of mutant SOD1 animals. Here, we were able to show that the association of misfolded SOD1 with the spinal cord mitochondria is increased in the absence of MIF even at the pre-symptomatic stage in the SOD1G85R mouse model of ALS, causing an acceleration of disease onset and disease end-stage of these mice. These results show a direct effect of misfolded SOD1 mitochondrial association on ALS disease course in vivo. These results were recently published in PNAS (Leyton-Jaimes et al, 2016).
In Aim 3 of the research, we proposed to determine whether increased synthesis or depletion of MIF affects misfolded mutant SOD1 accumulation and pathogenesis in mice. Here we were able to make very important progress. From our results, it is clear that mutant SOD1 mice with reduced expression levels of MIF have accelerated disease onset and end-stage and accumulate higher levels of misfolded SOD1. Moreover, these SOD1 mutant mice, which lack endogenous MIF expression, have higher levels of misfolded SOD1 associated with the ER and mitochondria specifically in the spinal cord. These results were published in the prestigious journal PNAS (Leyton-Jaimes et al, 2016). In addition, we are now doing one of the most interesting experiments of the proposed research plan; we are using adeno-associated virus to overexpress MIF in the CNS and we are testing how this increase of MIF levels affect the course of the disease in two different mouse models of ALS.
The proposed study has the potential to yield important information about misfolded SOD1 toxicity mechanisms. Moreover, the characterization of MIF as a novel chaperone for misfolded SOD1 opens new avenues for the development of ALS therapies.
As summarized above, during this grant we have made an important progress on the proposed research and we have published the results of the proposed research in the prestigious journals of Neuron and PNAS. A third article was published recently in ACS Chem. Neurosci. (Abu-Hamad et al, 2017) and a review which summarized part of the results was published in Exp. Neurol. (Leyton-Jaimes et al, 2017).
In addition, this grant helped me to receive additional funding. Moreover, I was able to present my research at national and international meetings where I made close contacts with world leading scientist in the field establishing new collaborations. This grant allowed me also to recruit graduate students and a postdoc to my lab to establish the first research group in Israel working exclusively on ALS research.