New Enzyme Identified as Potential Contributor to Parkinson's Disease Damage

Scientists at Nanyang Technological University (NTU Singapore) have identified a fat-producing enzyme in brain cells, glycerol-3-phosphate acyltransferase (GPAT), as a potential contributor to damage in Parkinson's disease. The research suggests that GPAT may amplify the detrimental effects of α-synuclein, a protein associated with the disease, by altering how brain cells process fats, thereby indicating a new target for potential treatments.

Discovery and Mechanism: Unraveling GPAT's Role

Researchers from NTU Singapore's Lee Kong Chian School of Medicine (LKCMedicine) discovered that GPAT interacts with α-synuclein, a protein known to accumulate in the brains of individuals with Parkinson's disease.

Researchers at NTU Singapore's LKCMedicine discovered that GPAT interacts with α-synuclein, a protein known to accumulate in Parkinson's brains, potentially increasing its harmful effects.

This interaction is proposed to increase the harmful effects of α-synuclein by modifying the fat processing within brain cells.

The study indicates that GPAT contributes to cellular damage by:

• Impairing mitochondria, the organelles responsible for energy generation in brain cells, which can reduce their energy capacity.
• Increasing the toxicity of α-synuclein.

These combined effects are reported to impact brain cells.

Experimental Findings: Evidence from the Lab

Laboratory experiments confirmed the impact of GPAT activity on cellular health. Scientists noted that reducing GPAT activity led to decreased brain cell damage in fruit flies and cultured mouse brain cells.

Scientists noted that reducing GPAT activity led to decreased brain cell damage in both fruit flies and cultured mouse brain cells.

Specific observations from the experiments include:

• Fruit flies engineered to produce excess human α-synuclein exhibited Parkinson's-like symptoms, such as impaired movement and loss of brain cells.
• Reducing the activity of the mino gene, which codes for GPAT, resulted in less brain cell loss, improved movement, and healthier activity patterns in these flies. Conversely, increased mino gene activity was associated with worsened symptoms.
• A compound named FSG67, which blocks GPAT activity, was tested. Treatment with FSG67 reportedly reduced the harmful effects of α-synuclein, including protein clumping and fat damage, in both fruit flies and laboratory-grown mouse brain cells.

Potential Therapeutic Implications

Professor Lim Kah Leong, Lead Investigator and Director of the Neuroscience & Mental Health Programme at NTU LKCMedicine, stated that these findings offer insights into how fat metabolism in brain cells influences α-synuclein toxicity, potentially opening new avenues for Parkinson's disease treatment.

"These findings offer insights into how fat metabolism in brain cells influences α-synuclein toxicity, potentially opening new avenues for Parkinson's disease treatment." - Professor Lim Kah Leong

Parkinson's disease is globally recognized as the second most common neurodegenerative disorder, affecting over 11 million people.

Professor Tan Eng King, an independent expert from the National Neuroscience Institute, commented that the study provides novel insights into the connection between metabolic dysregulation and brain dysfunction.

"The study provides novel insights into the connection between metabolic dysregulation and brain dysfunction... metabolic pathways could be relevant targets for brain disorders, particularly given the current absence of effective disease-modifying therapies for Parkinson's disease." - Professor Tan Eng King

Future Research Directions

The NTU team plans to conduct further validation of these findings and aims to explore the development of GPAT inhibitors as a new class of drugs for Parkinson's disease. Their future work also seeks to deepen the understanding of neurodegenerative processes and identify additional therapeutic strategies.