Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease caused by the death of motor neurons in the spinal cord and brain. ALS is a genetically complex disease; diverse mutations cause motor neuron death by disrupting various interrelated pathways. To date, no therapy targeting a single factor can rescue motor neuron loss, nor is it known how or why sub-populations of motor neurons are particularly vulnerable in disease. Many studies have pointed to the Transforming Growth Factor Beta (TGF-π±) signaling superfamily as a modifier of disease in human patients and in animal models. Here, we have used the SOD1G93A model of ALS to investigate if and how TGF-π± signaling in motor neurons changes pathology in these animals. In the first part of this study we characterize canonical TGF-π± activation in motor neurons in SOD1G93A animals compared to controls.
We have found that a vulnerable motor neuron subpopulation upregulates TGF-π±RII, a receptor necessary and unique to the classical arm of the TGF-π± signaling family, in a disease dependent manner. Despite the upregulation of TGF-π±RII in these cells, there is not a corresponding activation of downstream canonical TGF-π± effectors in diseased motor neurons. Through in vivo genetic manipulation we found that TGF-π±RII is dispensable in motor neurons, but that ablation of TGF-π±RI, a key receptor in multiple arms of the TGF-π± superfamily, decreases motor neuron survival in SOD1G93A animals. To further understand how this manipulation changes TGF-π± activation in motor neurons, we performed iterative indirect immunoflourescence imaging. We have identified that knocking out TGF-π±RI from motor neurons disrupts downstream canonical TGF-π± activation in these cells. To identify how TGF-π± signaling changes gene expression in these cells we have used Visium, a spatial RNAseq method, on lumbar spinal cords from these animals We have identified and are currently investigating potential downstream targets of TGF-π± signaling in motor neurons in SOD1G93A animals.
These data suggest that motor neurons rely on TGF-π± signaling for survival in disease and that TGF-π± signaling is important to the biology of a known vulnerable population of motor neurons.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/d8-mebp-f018 |
| Date | January 2022 |
| Creators | Braine, Catherine Elizabeth |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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