Possible approach to treating effects of neurodegenerative diseases – and even ageing – revealed by trial.
In work that could open a new front in the war on Parkinson’s disease, and even ageing itself, scientists have shown that they can stave off some of the effects of the neurodegenerative disease by flushing “zombie cells” from the brain.
The research in mice raises hopes for a fresh approach to treating the most common forms of Parkinson’s disease, which typically arise through a complex interplay of genetics, lifestyle and potentially toxic substances in the environment.
But the approach may have benefits far beyond Parkinson’s, with other neurodegenerative diseases – and the ageing process more broadly – all being linked to the ill effects of these “senescent” cells, which linger in tissues after entering a state of suspended animation in the body.
“It’s a completely new way of looking at neurodegenerative disease and finding potential drugs,” said Marco Demaria, a molecular biologist on the team at the University of Groningen in the Netherlands. “For most of these conditions, we don’t have any way to counteract them.”
Parkinson’s disease affects about 10 million people worldwide, and usually takes hold when certain types of neurons in the brain become impaired or die off completely. The neurons in question produce a substance called dopamine, which is crucial for enabling the brain to produce smooth and coordinated physical movements.
Demaria and scientists at the Buck Institute for Research on Aging in California suspected that other cells in the brain – the astrocytes which support the signal-carrying neurons – may be involved in Parkinson’s disease. Specifically, they thought astrocytes might cause problems when they became senescent, a state where cells stop dividing but release chemicals that drive up inflammation. This local inflammation, they thought, could be harming nearby neurons.
Writing in the journal Cell Reports, the scientists describe how brain tissue taken from dead Parkinson’s patients had more senescent astrocytes than healthy brain tissue. They also found that exposing human astrocytes to the herbicide paraquat flipped the cells from a healthy state into senescence. The transformation into the zombie-like state forms part of the body’s natural defences against cancer: when cells are in danger of uncontrolled growth, the switch to senescence keeps them in check.
To test whether senescent astrocytes might have a downside – and play a role in Parkinson’s disease – the scientists exposed six-month-old mice to paraquat, a weedkiller that has been linked to Parkinson’s disease in humans. The herbicide produced senescent astrocytes in the animals’ brains and tests showed they had physical difficulties moving around.
The scientists next looked at what happened when mice exposed to paraquat were injected with a drug that destroys senescent cells. The drug appeared to protect the mice and kept their movement problems at bay. “They are able to move around their cages well,” said Demaria. “They are almost indistinguishable from the healthy mice.”
The scientists suspect that the inflammatory chemicals released by senescent astrocytes are particularly damaging to neurons that make dopamine. But previous research has found they may affect health and the ageing process more generally. In 2016, Jan van Deursen at the Mayo Clinic in Minnesota showed that wiping out senescent cells made mice live 20% longer.
Demaria believes that flushing senescent cells from the brain could one day help protect humans from Parkinson’s and other neurodegenerative diseases, but said scientists need new drugs to target the right zombie cells. One hurdle they need to overcome is that while some senescent cells in the body seem to drive diseases of old age, largely by ramping up inflammation, other senescent cells are valuable, helping wounds to heal and more. “We know the cells we want to target, but at the moment we don’t have the therapeutics to do that. We cannot yet only target the bad cells.”
Prof David Dexter, deputy director of research at Parkinson’s UK, said: “Further research will therefore be needed to establish if senescence contributes to the loss of cells in people with Parkinson’s, but the discovery opens up a new avenue for therapies which may one day be able to slow or stop the progression of the condition.”