Parkinson’s disease (PD) is a brain disorder caused in major part by the toxic aggregation of a protein called alpha-synuclein which causes downstream loss of nerve cells. Current treatment options approved for people with PD act to compensate for the loss of normal nerve cell functions, but don’t stop the underlying reasons why they are lost in the first place.

One-way healthy cells normally clear excess alpha-synuclein is through lysosomes - tiny "waste disposal" centres inside our cells. Improper functioning of lysosomes is one problem which can contribute to toxic alpha-synuclein aggregation in PD.

The NSL-complex is a group of proteins that are responsible for controlling how much certain genes are expressed in the cell. Interestingly, two of the key components of this complex called KANSL1 and KAT8 have been genetically linked to PD risk. Our research has shown that KANSL1 and KAT8 control the expression of PD-related genes including many that are essential for lysosome health. Enhancing the activity of these two proteins could therefore help protect brain cells from damage in PD.

In this project, I will investigate which genes are regulated by the NSL-complex in different brain cell types and how impairments in KANSL1 and KAT8 can affect their health. I will also explore a potential gene therapy approach to enhance the protective effects of the NSL-complex. Using brain cell models of PD, I will test whether boosting NSL-complex activity can improve lysosome function and protect against toxic alpha-synuclein buildup.

If successful, this research could lay the foundations for new disease-modifying therapies that help safeguard nerve cells and slow the progression of PD by tackling some of its underlying root causes.