Direct Astrocyte-To-Neuron Conversion in Spinal Neurodegenerative Disease Models

Open Access
- Author:
- Keefe, Matthew George
- Area of Honors:
- Biochemistry and Molecular Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Dr. Gong Chen, Thesis Supervisor
Craig Eugene Cameron, Thesis Honors Advisor - Keywords:
- NeuroD1
neurodegenerative disease
spinal cord injury
ALS
neuroscience
transdifferentiation - Abstract:
- Neurodegenerative diseases such as spinal cord injury (SCI) and amyloid lateral sclerosis (ALS) are well-known not only for their debilitating effects, but also for the difficulties of modern medicine to treat them. With the advent of gene therapy and specific cell fate determination of stem cells, there is widespread interest in generating neurons in situ for the treatment of neurodegenerative diseases such as these. Here, I present the effects of viral delivery of NeuroD1, a transcription factor previously shown by the lab to convert glial cells to neurons in the brain (Guo et al., 2014). In the healthy spinal cord, SCI model, and ALS model, injection of NeuroD1 generated cells with neuronal morphology positive for neuronal marker NeuN, whereas cells infected with control virus retained glial identity. At early timepoints following NeuroD1 injection, transitional cells with both astrocytic and neuronal markers were observed, indicating direct conversion as a result of NeuroD1. Furthermore, NeuroD1 targeted towards cortical neurons was able to upregulate NeuroD1 in existing neurons with projections through the corticospinal tract into the cervical spinal cord, where it had a potential beneficial impact on astrocyte pathology. Together, these results suggest that overexpression of NeuroD1 in the spinal cord is sufficient to convert astrocytes to neurons in both SCI and ALS mouse models, presenting a potential new therapy for these diseases.