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Effect of Dietary Ketosis On Alpha-Synuclein Accumulation

Study Rationale:
A key feature of Parkinson’s disease is abnormal accumulation of the protein alpha-synuclein. Production of organic compounds called ketones is a normal metabolic process that occurs when glucose availability is low, such as during calorie restriction and in low-carbohydrate diets. Ketones stimulate the breakdown of proteins in the liver. Therefore, it is possible that ketone production could help to reduce abnormal accumulation of alpha-synuclein in Parkinson’s disease.

Our central hypothesis is that increased ketone production induced through dietary carbohydrate restriction will cause a reduction in abnormal accumulation of the protein alpha-synuclein in the brain and improve motor and cognitive function in pre-clinical models that over produce human alpha-synuclein.

Study Design:
Experimental models that overproduce the protein alpha-synuclein, a genetic model of Parkinson’s disease, and models that produce normal amounts of alpha-synuclein will be fed either a low-carbohydrate diet or a control diet for 28 days starting at two months of age. After, all models will be tested for motor, attention and memory function. Following behavior testing, we will measure ketone levels in blood and abnormal accumulation of the alpha-synuclein in brain. In addition, proteins involved in the breakdown of alpha-synuclein will be measured in the brain.

Impact on Diagnosis/Treatment of Parkinson’s Disease: 
The low-carbohydrate diet, also known as the ketogenic diet, is already used clinically in children with epilepsy. Therefore, it is an established safe application in people and would be easily applied to Parkinson’s patients.

Next Steps for Development:
The next important steps will be to test the long-term effect of the ketogenic diet on behavior and abnormal alpha-synuclein and to test whether administration of ketones alone can improve behavior and reduce abnormal alpha-synuclein.

Final Outcome

A key feature of Parkinson's disease (PD) is the abnormal accumulation of protein alpha-synuclein in the brain. Reduction in alpha-synuclein accumulation in the brain may have therapeutic benefit in PD. The present study examined the effect of a ketogenic diet, which requires low carbohydrate and high fat consumption, on movement and cognition and on accumulation of alpha-synuclein in the brains of pre-clinical models with Parkinson's features. Models that overproduce alpha-synuclein and those that produce normal amounts of the protein received either a low-carbohydrate diet or a regular diet for 28 days. Movement and cognition were evaluated one month after starting the diet. Alpha-synuclein and proteins related to its breakdown were also measured in the brain at that time. In models that overproduce alpha-synuclein, cognition improved on the ketogenic diet, but movement did not. In these models, the ketogenic diet significantly reduced alpha-synuclein clumps -- the pathological hallmark of PD -- in the substantia nigra, a brain region that loses cells in Parkinson's. In the brains of models that produce normal amounts of alpha-synuclein, the ketogenic diet significantly reduced the accumulation of the protein as well. In addition, in models receiving the ketogenic diet proteins associated with the breakdown of alpha-synuclein differed from those in models on the regular diet. Additional studies are needed to further understand how the low-carbohydrate, high-fat diet reduces alpha-synuclein accumulation in the brain.


  • Sheila Marie Fleming, PhD

    Cincinnati, OH United States

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