Blocking enzyme cuts toxic Parkinson’s effects in models, University of Cambridge researchers discover

Researchers in Cambridge have identified a key enzyme that drives Parkinson’s disease and have shown that blocking it restores normal functions in animal and cell models.

The breakthrough offers a promising new target for treatment of the disease, although there are challenges to overcome first.

In Parkinson’s, the protein alpha-synuclein builds up in clumps called Lewy bodies in nerve cells in the brain, stopping them from functioning normally and eventually causing the cells to die.

One way our bodies usually rid themselves of toxic materials like these is via the process of autophagy, through which cells break down and recycle unwanted components. But autophagy does not work properly in Parkinson’s, so the cells are unable to get rid of the toxic alpha-synuclein.

Now a study led by Dr Sung Min Son and colleagues in Professor David Rubinsztein’s lab, at the UK Dementia Research Institute (UK DRI) at the University of Cambridge, has uncovered a pathway involving the enzyme ACLY that is hyperactivated in Parkinson’s.

Initially using human cells, including brain cells and organoids – mini-brains grown in the lab – that contained abnormal alpha-synuclein, and then using zebrafish and mouse models, they showed that abnormal alpha-synuclein over-activates ACLY.

This causes a cascade of events in nerve cells, disrupting autophagy, which leads to the accumulation of alpha-synuclein and the cellular stress and damage seen in Parkinson’s.

The researchers showed that blocking the function of ACLY restored normal autophagy and reduced levels of the toxic alpha-synuclein in cells and mini-brains.

In the zebrafish and mouse models, which had been genetically altered to carry a mutation in the alpha-synuclein gene that causes Parkinson’s in humans, using drugs to block the function of ACLY similarly boosted autophagy and led to increased removal of alpha-synuclein. In these animal models, this successfully reduced the disease-associated effects, suggesting a potential strategy to target a root cause of cell death in Parkinson’s.

Prof Rubinsztein, group leader at the UK DRI at Cambridge, said: “Our research shows that ACLY acts like a switch, triggering a series of changes inside brain cells, that we believe are central to Parkinson’s progression. A key finding is that when we blocked ACLY, we were able to reverse many of these changes, not just in human brain cells, but also in zebrafish and mouse models.

“This suggests that problems caused by alpha-synuclein in Parkinson’s aren’t just about the protein itself, but how it disrupts other processes within cells. Our research suggests that ACLY is a compelling drug target for Parkinson’s, laying the foundation for future therapies aimed at halting or reversing the course of the condition.”

But another challenge remains to be solved.

Several compounds block, or inhibit, ACLY, including hydroxycitrate – a controversial weight-loss supplement.

Other compounds that inhibit ACLY have been evaluated as potential anti-cancer therapeutics.

But these compounds do not cross the blood-brain barrier, so the next step for the researchers is to develop an ACLY inhibitor that can pass into the brain from the blood.

The study was funded by the UK DRI, Parkinson’s UK, Rosetrees and the John Black Charitable Foundation and published in the journal Neuron.