Investigation of Striatal Astrocytes to GABAergic Neuron Conversion In Vivo in Huntington’s Disease Mouse Model
Open Access
- Author:
- Xu, Kevin
- Area of Honors:
- Biology
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Aimin Liu, Thesis Supervisor
Bernhard Luscher, Thesis Honors Advisor - Keywords:
- ND1
Dlx2
Huntington's Disease
HD
GABAergic neurons
transcription factors
gene therapy
striatal astrocytes
R6/2 mouse model
astrocyte-to-neuron conversion
ND1
Dlx2
Huntington's Disease
HD
GABAergic neurons
transcription factors
gene therapy
striatal astrocytes
R6/2 mouse model
astrocyte-to-neuron conversion - Abstract:
- Huntington’s disease is an inherited autosomal dominant neurodegenerative disease due to a CAG trinucleotide repeat expansion in the huntingtin gene which leads to excessive polyglutamine sequence stretch, resulting in behavioral and motor deficits from the decrease in striatal GABAergic neurons. The human brain is incapable of sufficient self-repair in either removing the toxic gain of function or regenerating GABAergic neurons. Thus, a possible therapeutic solution to address this deficit would be to replace the neuronal death and dysfunction with new neurons. In this lab, I have analyzed the in vivo conversion technology for AAV-mediated ectopic expression of Neuronal Differentiation 1 (ND1) and Distal-Less Homeobox 2 (Dlx2) transcription factors to convert striatal astrocytes to GABAergic neurons in the R6/2 HD mouse model. Under the transgenic mice model, the R6/2 mouse line’s expression of a 1.9-kb fragment from the 5’ UTR sequence and exon 1 could accurately reproduce the severe anatomical and behavioral symptoms present in Huntington’s disease such as motor abnormalities along with the reduction in neuron concentration in the striatum. Through intracranial and retroorbital injections with the ND1 and Dlx2 treatment, there was evidence of striatal astrocyte conversion into GABAergic neurons. Furthermore, behavioral tests indicated that motor function, spatial learning, and weight loss improved for R6/2 mice treated with ND1 and Dlx2. Given these preliminary results, the astrocyte-to-neuron conversion technology with ND1+Dlx2 transcription factors could potentially be a gene therapy to treat Huntington’s disease along with other neurodegenerative diseases; however, further experiments and studies of the treatment outcomes and mechanism need to be conducted in order to better understand its potential and limitations.