Cell cycle dysregulation in iPSC‐derived neurons from C9ORF72 carriers
Rodrigo Lopez Gonzalez- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
The GGGGCC (G4C2) repeat expansion in the C9ORF72 is the most common genetic form of amyotrophic lateral sclerosis (ALS). We and others have uncovered the role of DNA damage, upregulation of the NHEJ repair pathway and P53 activation in the pathogenesis of C9ORF72‐related ALS. Evidence from other neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease, suggests cell cycle re‐entry of post‐mitotic neurons may be detrimental and contribute to neurodegeneration.
Method
In this study, we used several well characterized induced pluripotent stem cells (iPSC) from C9ORF72 carriers and controls and differentiate into neurons. iPSC‐derived neurons were cultured for up to two months and analyzed at different time points by gene expression and western blot analysis.
Result
We have found an age‐dependent increase in the levels of cell division markers including Ki67 and Geminin (GMNN) as well as Cyclin A2, Cyclin B1, Cyclin B2, CDK1, CDK2 and CDK4 in 2‐month‐old neurons from C9ORF72 carriers as compared to controls. When we analyzed 1‐month‐old neurons as we did not find differences between controls and C9ORD72 neurons. Moreover, we found a decrease in the levels of p21 is a cyclin‐dependent kinase inhibitor that belongs to the CIP/Kip family of CDKs inhibitors and has the ability to arrest cell cycle progression at G1/S and G2/M stages, this data indicate dysregulation of cell cycle in C9ORF72 neurons.
Conclusion
Our data indicates that post‐mitotic neurons from C9ORF72 repeat expansion carriers are aberrantly activating the expression of proteins related to cycle progression.