GIST Proposes Strategy to Alleviate Progression of Parkinson's Disease by Blocking Core Pathological Pathways

From the left, Professor Changmyung Oh and Dr. Eunkyung Lee from the Department of Biomedical Science.

Gwangju Institute of Science and Technology (GIST) announced on March 23 that the research team led by Professor Changmyeong Oh of the Department of Biomedical Science has proposed a new therapeutic strategy for alleviating the progression of Parkinson's disease by inhibiting the production of a specific lipid component in brain cells called ceramide.

Parkinson's disease, which affects about 10 million people worldwide, is a neurodegenerative disorder that gradually leads to the loss of motor functions, such as hand and foot tremors and gait disturbances. Currently, most treatments focus on alleviating symptoms, and there is still no medication that addresses the root cause of the disease. In particular, because nerve cells are progressively damaged over several years, significant neurological damage has often already occurred by the time symptoms appear.

The research team focused on 'ceramide,' a substance that acts like a lipid within brain cells and regulates cell structure and signal transmission. Ceramide is known to accumulate abnormally in aging and neurodegenerative diseases and, in particular, plays a role in promoting the aggregation of the 'alpha-synuclein' protein, which damages nerve cells in Parkinson's disease.

In fact, through comparative analysis of brain tissue from six patients with Lewy body dementia (LBD) and six normal brain samples, the research team found that 19 types of ceramide were significantly increased in the patient brains. In addition, genetic analysis confirmed that the activity of genes related to enzymes (including CERS5 and CERS6) that produce ceramide in dopaminergic neurons was also increased.

Recovery Effects of Myriosin on Pathology and Behavior in Parkinson's Disease Mouse Model.

The research team then validated the effect of inhibiting ceramide production using animal models of Parkinson's disease and patient-derived cells. When the compound 'myriocin,' which inhibits ceramide synthesis, was administered for 5 to 7 months to experimental mice in which alpha-synuclein protein was abnormally aggregated, it resulted in a decrease in protein aggregation, improvement in motor and memory functions, and a significant reduction in damage to dopaminergic neurons.

Furthermore, this drug (myriocin) was shown to reduce the expression of inflammation-related genes and to restore the signal transmission function of dopaminergic neurons, which control movement, memory, and concentration, to near-normal levels. The process of mitophagy—the removal of damaged mitochondria within the cell—was activated, while neuroinflammation and cell death were also reduced. These effects are attributed to the activation of mitophagy, suggesting that this process is a key mechanism in improving the pathology of Parkinson's disease.

The research team also conducted the same experiments using 'midbrain organoids' (miniature brain tissue) derived from patient stem cells and actual patient-derived neurons. The results consistently showed that administration of myriocin led to reduced aggregation of alpha-synuclein protein and increased survival of dopaminergic neurons. Conversely, when ceramide was externally supplemented, protein aggregation and neuronal damage increased again, providing direct evidence that ceramide accumulation is directly involved in the core pathology of Parkinson's disease—namely, protein aggregation and neuronal damage.

Professor Changmyeong Oh stated, "The significance of this study lies in presenting the possibility of blocking the fundamental pathways of the disease that lead to protein aggregation and neuronal death, rather than simply alleviating symptoms," adding, "We plan to continue our research to develop safer synthetic inhibitors and conduct long-term toxicity testing for future clinical application."

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