New Insights into Parkinson's Disease Reveal Potential Treatment Target

Recent research has unveiled a significant metabolic driver associated with Parkinson's disease, providing a promising new target for therapeutic intervention. The study, published in the journal Neuron, highlights the role of an enzyme known as ACLY, which has been found to be hyperactivated in patients suffering from this neurodegenerative condition.

In Parkinson's disease, the accumulation of a protein called alpha-synuclein leads to the formation of clumps known as Lewy bodies within brain cells. These aggregates disrupt normal cellular functions, ultimately resulting in cell death. One critical cellular process that typically helps eliminate such toxic materials is autophagy, where cells break down and recycle unwanted components. However, this mechanism appears to malfunction in individuals with Parkinson's, preventing the effective clearance of harmful alpha-synuclein.

Led by a team at the UK Dementia Research Institute at the University of Cambridge, researchers investigated human cells, including neurons and organoids (miniature brain models), to examine the relationship between alpha-synuclein and ACLY. The findings demonstrated that abnormal alpha-synuclein hyperactivates ACLY, initiating a cascade of cellular events that disrupt autophagy. This disruption contributes to the accumulation of alpha-synuclein and the associated cellular stress characteristic of Parkinson's.

The study's results indicated that inhibiting ACLY restored normal autophagy and decreased levels of toxic alpha-synuclein in various models, including human cells, organoids, zebrafish, and mice. By using pharmacological agents to inhibit ACLY, the researchers successfully diminished the toxic effects of alpha-synuclein in brain cells and organoids. Moreover, in genetically modified zebrafish and mice that exhibit an alpha-synuclein mutation linked to Parkinson's in humans, ACLY inhibition improved autophagy and facilitated the clearance of alpha-synuclein.

These findings suggest a novel disease-modifying approach that targets the underlying causes of cell death in Parkinson's disease. Several compounds known to inhibit ACLY exist, including hydroxycitrate, a substance often used in weight-loss supplements. However, a significant hurdle remains: many of these compounds struggle to cross the blood-brain barrier. Therefore, future research will focus on developing ACLY inhibitors capable of effectively entering the brain.

According to the lead researcher, the study reveals that ACLY functions as a regulatory switch within brain cells, instigating a sequence of changes central to the progression of Parkinson's disease. Importantly, blocking ACLY not only reversed many detrimental changes in human brain cells but also in animal models, reinforcing the enzyme's potential as a therapeutic target.

This research underscores that the challenges posed by alpha-synuclein in Parkinson's disease extend beyond the protein itself, implicating broader disruptions in cellular processes. The identification of ACLY as a drug target paves the way for future therapies aimed at halting or even reversing the progression of Parkinson's disease.