- Topoisomerases play significant roles in neuronal function and their dysfunction has been increasingly linked to various neurodegenerative conditions. Type IB and Type II topoisomerases are particularly important in neurons due to their role in managing topological stress during transcription of long genes, which are abundant in neural tissues.
- Research has revealed a strong connection between topoisomerases and several neurodegenerative disorders, particularly those involving long genes associated with synaptic function and neural development. Topoisomerase I has been shown to be crucial for the expression of extremely long genes (>100 kb), many of which are involved in neural development and function. Disruption of this process can lead to neurological dysfunction.
- In Alzheimer’s disease, topoisomerase dysfunction has been linked to genomic instability and DNA damage in neurons. The accumulation of DNA damage, particularly double-strand breaks, may contribute to neuronal death and cognitive decline. Additionally, topoisomerase I has been implicated in the regulation of genes involved in amyloid-β processing and tau phosphorylation.
- Studies in Parkinson’s disease have shown that topoisomerase I inhibition can lead to decreased expression of α-synuclein and other long genes involved in dopaminergic neuron function. This suggests that proper topoisomerase activity is essential for maintaining healthy dopaminergic neurons, which are primarily affected in Parkinson’s disease.
- In autism spectrum disorders, mutations affecting topoisomerase function have been associated with altered expression of genes crucial for neurodevelopment. The TOP1 gene has been identified as a high-confidence autism spectrum disorder risk gene, highlighting the importance of proper topoisomerase function in neural development.
- Recent evidence suggests that topoisomerases may also play a role in repeat expansion diseases, such as Huntington’s disease and various ataxias. These enzymes may influence the stability of repeated DNA sequences, potentially affecting disease progression.
