Northwestern Medicine investigators have uncovered new insights into how metabolic dysfunction contributes to Parkinson’s disease, according to a study published in Nature Communications.
Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the center of the brain that controls movements. These neurons have high energy demands, making them especially vulnerable to mitochondrial dysfunction — a breakdown of the cell’s power source and a key driver of oxidative stress.
“Prior studies have revealed mitochondrial dysfunction to be a driver of Parkinson’s disease, but the molecular mechanisms through which mitochondrial metabolic pathways contribute to the pathogenesis of PD have been largely unknown,” said Dimitri Krainc, MD, PhD, the Aaron Montgomery Ward Professor and chair of the Ken and Ruth Davee Department of Neurology, and senior author of the study.
A subset of Parkinson’s disease is caused by CHCHD2, a gene which encodes a protein contained in the mitochondria of cells. In the current study, Krainc and his collaborators sought to better understand how CHCHD2 impacts cellular metabolism in Parkinson’s disease.
First, investigators examined the mitochondrial metabolism by performing an unbiased metabolomic analysis of purified mitochondria. They found that alpha-ketoglutarate dehydrogenase (alpha-KGDH), an enzyme that plays a critical role in metabolism regulation, was impaired.
“This deficiency of KGDH resulted in disrupted conversion of alpha-KG to downstream succinate in the TCA cycle, accompanied by a decrease in mitochondrial respiration — a key reaction in ATP production,” Krainc said.
The investigators then demonstrated that the dysregulation of this metabolic pathway led to increased lipid peroxidatio — a process that damages cellular membranes and may trigger neuronal death.
Finally, investigators treated the dopaminergic neurons with lipoic acid and were able to reduce lipid peroxidation and prevent the accumulation of alpha-synuclein. The accumulation of this protein is a key feature of Parkinson’s disease.
The results of the study open the door for new potential therapies, Krainc said.
“The findings highlight an important role of dysregulated mitochondrial metabolism in the pathogenesis of Parkinson’s disease and suggest a therapeutic approach through targeting of alpha-ketoglutarate dehydrogenase,” Krainc said.
Moving forward, Krainc and his collaborators will continue to study this metabolic pathway in other forms of Parkinson’s disease.
Ge Gao, PhD, a postdoctoral fellow in the Krainc laboratory, was the first author of the study. Co-authors included Han-Xiang Deng, PhD, research professor of Neurology in the Division of Neuromuscular Disease, and Yong Shi, PhD, a research associate in the Deng laboratory.
This work was supported by National Institutes of Health grants R35 NS122257, R01 NS099623 and R21 NS114765.
