Date of Award
2020
Embargo Period
12-10-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Cell and Molecular Pharmacology and Experimental Therapeutics
College
College of Graduate Studies
First Advisor
Mariana Pehar
Second Advisor
Lauren Ball
Third Advisor
Joe. B Blumer
Fourth Advisor
Hainan Lang
Fifth Advisor
Kumar Sambamurti
Abstract
Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of both upper and lower motor neurons. Astrocytes are key for maintaining central nervous system homeostasis and are important determinants of motor neuron fate in ALS. Accordingly, IPSC-derived astrocytes from ALS patients or astrocytes from diverse ALS mouse models, including mice overexpressing the ALS-linked mutant hSOD1G93A, induce motor neuron death in co-culture. Previously our lab reported that motor neurons isolated from receptor for advanced glycation end products (RAGE) knockout mice are resistant to the ALS-astrocyte derived neurotoxicity. Therefore, our working hypothesis states that inhibition of RAGE signaling can suppress astrocyte-mediated neurotoxicity and has potential translational value to prevent or delay ALS disease progression. We confirmed that in a co-culture model, the motor neuron death induced by ALS-astrocytes is prevented by RAGE pharmacological inhibition (FPS-ZM1 or RAP). RAGE inhibition also prevented the motor neuron death induced by lumbar spinal cord extracts from symptomatic hSOD1G93A mice. To confirm the relevance of this neurotoxic mechanism in ALS pathology, we evaluated the therapeutic potential of FPS-ZM1 in vivo in hSOD1G93A mice. FPS-ZM1 treatment significantly improved hind-limb grip strength of hSOD1G93A mice during the progression of the disease. This was associated with improved survival of large motor neurons, reduced gliosis, and decreased ER stress in the spinal cord. Moreover, FPS-ZM1 reduced the expression of atrophy markers in the gastrocnemius muscle. However, RAGE inhibition did not alter the onset of the disease nor the survival of hSOD1G93A mice significantly. The maintenance of hind-limb grip strength was also observed in hSOD1G93A mice with genetic RAGE haploinsufficiency, further indicating the beneficial effect of RAGE inhibition on motor function. However, this beneficial effect was not observed in mice with complete RAGE ablation. Moreover, the partial or complete RAGE ablation drastically shortened the median survival of hSOD1G93A mice by 14 and 18 days, respectively. These results reveal a complex effect of RAGE inhibition in hSOD1G93A mice. Together, our data indicate that the development of therapies targeting RAGE in ALS require better understanding of its role, in a cell type- and stage-specific manner, during the progression of the disease.
Recommended Citation
Liu, Liping, "RAGE Signaling as a Pharmacological Target in Amyotrophic Lateral Sclerosis" (2020). MUSC Theses and Dissertations. 743.
https://medica-musc.researchcommons.org/theses/743
Rights
All rights reserved. Copyright is held by the author.