Yulan Xiong, an associate professor at UConn Health, and her team have made significant strides in understanding Parkinson's Disease by uncovering a crucial genetic factor that could lead to new treatment options.

Notably, a mutation in the LRRK2 gene is recognized as the most common genetic cause of Parkinson's Disease, impacting around one million Americans.

While the association of LRRK2 mutations with Parkinson's Disease is well-established, the precise mechanisms that trigger the disease's progression remain largely unclear.

Xiong highlights that the GTPase domain of LRRK2 is an understudied area in Parkinson's research, with much of the previous focus being on the more accessible kinase domain.

LRRK2 comprises two enzyme domains: the kinase domain, which is easier to target for drug development, and the GTPase domain, which is critical yet more challenging to modulate.

In her earlier research, Xiong identified that the enzyme ATIC and its substrate AICAR regulate LRRK2 at the mRNA level, with ATIC being overactive in Parkinson's patients, resulting in excessive production of the protein dardarin.

The research team has identified a regulator capable of switching LRRK2's GTPase function on or off, presenting a promising therapeutic target to slow the progression of Parkinson's.

Their latest findings, published in Science Advances, reveal a new key regulator, CalDAG-GEFI (CDGI), which can inhibit the overactivity of LRRK2.

The ultimate goal is to develop an inhibitor that specifically regulates LRRK2 activity, building on previous discoveries related to LRRK2 protein expression.

Xiong's research has utilized cell and mouse models, with plans to expand studies to include human samples.

Additionally, collaboration with an external company is underway to create a small molecule capable of penetrating the blood-brain barrier to deliver potential therapies.