PTEN deletion makes healthy, happy neurons. One more step along the path.
We’ve been reporting regularly on our progress in the CST/PTEN project to develop interventions to regenerate nerve connections (axons) after spinal cord injury (SCI). The latest advance is described in a paper by Erin Gutilla, an M.D./Ph.D. student in Os Steward’s lab, reporting that long-term deletion of PTEN in neurons not only isn’t harmful; it causes neurons to grow and...well, look young again.
PTEN negatively regulates an intracellular signaling pathway called AKT/mTOR. In early development, the pathway is turned on by growth factors acting through receptors, which stimulates cell division and cell growth. As organisms mature to adulthood, PTEN turns on and shuts down AKT/mTOR. So, deleting PTEN takes the brakes off of the growth-promoting AKT/mTOR pathway, which enables nerve cells to regenerate their axons after spinal cord injury. In essence, what PTEN deletion seems to do is turn back the developmental clock to make neurons into early teenagers in a growth spurt.
Like almost every powerful therapy, however, there are potential concerns. Turning nerve cells into early teenagers primes them for a growth spurt, but as we all know, teenagers can be difficult. Parents sometimes may wonder whether an alien has taken over a teenager’s body. I could go on, but enough on that…
One concern was that deleting PTEN might increase the risk of tumors. PTEN is a tumor suppressor gene. Mutations in PTEN have been identified in many cancers, and mutating PTEN in early development can cause overgrowth of the brain, called macrocephaly. For these reasons, it was important to determine whether there were negative consequences of deleting PTEN in nerve cells in the way that was needed to induce regeneration.
In the study that just came out (Gutilla et al., 2016) we deleted PTEN in 1 day old mice and then examined their brains when they were up to 1.5 years old. The lifespan of mice is a bit over 2 years, so 1.5 years is the equivalent of retirement age. Importantly, there was no evidence of any neuropathology or tumors. Instead, the neurons lacking PTEN actually were larger and more healthy-looking than neurons in other parts of the brain (Figure), and looked like neurons in young adult mice. It was as if the aging clock had been turned back.
The lack of any detectable neuropathology due to PTEN deletion is very good news, suggesting that long-term deletion of PTEN selectively in neurons may have relatively low risk. Of course, there will need to be more safety testing but this is an encouraging assessment.
The broader implication of these findings is that targeting PTEN may be a way to reduce neuronal atrophy and death in neurodegenerative diseases like Parkinson’s disease, Alzheimer’s Disease, and ALS and even reverse “normal” age related deterioration of neurons. Erin Gutilla will be completing her dissertation research in the next year by exploring these questions.
