To date all genetic studies have focused on only one percent of the human genome. Whereas 40% of the human genome consists of transposable elements and 8% is retroviral sequences. Most of these are repeat sequences and have been termed junk DNA. Many of these genes are specific to humans. Their role in mediating neurodegenerative disorders and neurodevelopment has only recently been considered.

We have explored the role of endogenous retroviruses in early embryonic development, neurodevelopmental tumors and in neurodegenerative diseases using a variety of in vitro models, in vivo systems, animal models and human studies.

We found that the envelope protein of a human endogenous retrovirus-K (HERV-K/ HML-2) was expressed at a critical stage of embryonic development and was important for mediating stemness by triggering secondary signaling pathways important for cell division and survival. The virus was very tightly regulated during neurodevelopment and silenced in neurons. Neurodevelopmental tumors showed unchecked upregulation of expression of the HERV-K envelope and inhibition of which paralleled decrease in cell proliferation. Forced expression of HERV-K in terminally differentiated neurons resulted in cell death. We found increased expression of HERV-K in the brains of nearly one third of the patients with ALS. Mice in which HERV-K envelope was expressed in cortical neurons developed an ALS like phenotype that could be blocked by an sh-RNA to the HERV-K env. The significance of these findings will be discussed in the context of findings by other groups showing dysregulation of other transposable elements in ALS and Alzheimer’s disease.

Many of the human endogenous retroviruses are unique to humans and play a critical role in human development. They get silenced once organ development has occurred. However, unchecked expression can contribute to neurodevelopmental tumors and reactivation in adult brain can result in neurodegenerative disorders such as a subset of ALS. These elements likely have a broader role in neurodegenerative diseases that needs to be explored.