A groundbreaking study has uncovered a pivotal enzyme, ACLY, that plays a crucial role in the progression of Parkinson's disease. Researchers have demonstrated that inhibiting this enzyme can restore normal cellular function in both animal and cell models, presenting a promising new avenue for drug development. The research highlights how blocking ACLY enhances the body's natural process of autophagy, enabling cells to eliminate harmful alpha-synuclein proteins associated with Parkinson's.

In Parkinson's disease, the accumulation of alpha-synuclein proteins forms toxic clumps known as Lewy bodies within brain neurons. This buildup disrupts normal cellular functions and eventually leads to cell death. One mechanism by which the body clears such harmful materials is autophagy, where cells break down and recycle unwanted components. However, in Parkinson's patients, this process malfunctions, preventing the removal of toxic alpha-synuclein.

Dr. Sung Min Son and his team at the UK Dementia Research Institute (UK DRI) at the University of Cambridge discovered an enzymatic pathway involving ACLY that becomes excessively activated in Parkinson's. Their investigation revealed that abnormal alpha-synuclein overstimulates ACLY, triggering a cascade of events that impair autophagy. This disruption results in the accumulation of alpha-synuclein and subsequent cellular stress and damage characteristic of Parkinson's.

The researchers conducted experiments on human cells, including brain cells and organoids, along with zebrafish and mouse models containing mutated alpha-synuclein genes responsible for Parkinson's in humans. They found that by using drugs to inhibit ACLY, they could reduce the toxicity of alpha-synuclein in these models. In genetically modified zebrafish and mice, blocking ACLY enhanced autophagy, leading to increased removal of alpha-synuclein and mitigating disease-related effects.

This study suggests that targeting ACLY could serve as a potential strategy to modify the course of Parkinson's by addressing its root cause. Although several compounds exist that inhibit ACLY, such as hydroxycitrate, none effectively cross the blood-brain barrier. Thus, the next step involves developing an ACLY inhibitor capable of entering the brain from the bloodstream.

Professor David Rubinsztein emphasized that ACLY acts as a trigger for changes within brain cells central to Parkinson's progression. By inhibiting ACLY, the researchers successfully reversed many of these changes across different models, indicating that issues caused by alpha-synuclein extend beyond the protein itself. This discovery positions ACLY as a compelling target for future Parkinson's therapies aimed at halting or reversing the condition.

The findings offer hope for innovative treatments that may significantly impact the progression of Parkinson's disease, potentially transforming the lives of millions affected worldwide.