A Novel Gene and Mitochondrial Dysfunction Causing Familial Parkinson’s Disease Published in the Leading Journal Brain

The team led by Professor Chin-Hsien Lin (林靜嫻) and Professor Ruey-Meei Wu (吳瑞美), the Department of Neurology, the National Taiwan University Hospital, identified a novel gene and related mitochondrial dysfunction that cause familial Parkinson's disease. The study was published in the leading journal Brain.

Parkinson's disease is a common neurodegenerative disorder. With rapid population aging in the world, the World Health Organization has estimated that the number of people afflicted with this neurodegenerative disorder will increase from 4 million in 2005 to 9 million in 2030. Clinical symptoms of Parkinson’s disease include tremor, slowed movement, rigidity of the limbs, and impaired postural balance.  The most significant pathological feature is the degeneration of dopamine neurons, and the lack of dopamine leads to slowed locomotor functions. Although there is symptomatic benefit from dopaminergic treatment and deep brain stimulation therapy, there is currently no cure.  The condition will deteriorate with the age. Clarifying the mechanism for the pathogenesis of the disease and finding mechanism-targeted therapy is presently the key task.

The pathogenesis of Parkinson's disease is mutations in the predisposed genes, interplaying with environmental risk factors and aging, resulting in the apoptosis of dopamine neurons.  Clinically nearly 10% of patients has a family history of parkinsonism or with early onset age of disease.  Presently more than 30 genes have been identified in families with familial Parkinson’s disease. Exploring the role played by proteins downstream from these genetic puzzles in neurons will help to clarify the pathogenesis of Parkinson's disease. This research team has conducted the first comprehensive cohort study on the genes and clinical phenotypes of early onset or familial Parkinson’s disease in Asia, and has successfully clarified the blueprint of pathogenic gene mutations affecting these patients in Taiwan in the past (Lin CH et al., Mov Disorders, 2019 Apr;34(4): 506-515.). The team further used whole exome sequencing analysis to study a family with autosomal-dominant inherited Parkinson’s disease combined with polyneuropathy, but without known gene mutations mentioned above, and compared the results with gene analyses of nearly 500 families with Parkinson’s disease in Japan and Korea. A novel gene UQCRC1 (Ubiquinol-Cytochrome C Reductase Core Protein 1) was identified as the cause of hereditary Parkinson's disease in this family. This is a core protein of complex III in the mitochondrial electron transport chain. The team used CRISPR/Caspase 9 technique to introduce this genetic mutation into cell, Drosophila and mice models to study its pathogenesis.  The results showed that this mutation of the protein of complex III in the mitochondrial electron transport chain led to mitochondrial dysfunction and increased oxidative free radicals in cells, and progressive neurological function degeneration and locomotor defects with age (Lin CH et al., Brain, 2020 Dec 5;143(11):3352-3373).  This study by the team has demonstrated the pivotal role mitochondrial function plays in the pathogenesis of Parkinson’s disease, and has further identified the significance of the function of complex III in the mitochondrial electron transport chain, for the survival of dopamine neurons and the pathogenesis of Parkinson’s disease.

The team is committed to developing therapeutic strategies to optimize mitochondrial function in neurons, hoping to decelerate the degeneration of dopamine-related nervous system during the early stage of Parkinson’s disease, or even during the prodromal phase, and to shed light on treatments targeting pathogenic mechanism for patients with Parkinson’s disease, thereby lightening the burden of aging on the society.

Researchers participating in this study included Han-Yi Lin , Jieh Cheng, Meng-Lin Chen,  Yi-Ci Ko, in partnership with Professors Chih-Chiang Chan, Shiou-Ru Tzeng, Sung-Tsang Hsieh, Drs. Ni-Chung Lee, Dr. Ruoh-Fang Yen, Dr. Chi-Chao Chao, Dr. Hsin-Hsi Tsai, Dr.Hsin-Rong Lai, Yu-Chien Hong, Wen-Jun Luo, and Dr. Cheng-Yen Huang, Professor Shu-Hwa Lin, and Dr. Yi-Hsin Yow of the Core Lab I, the Branch Office of Research and Development, College of Medicine, National Taiwan University
Please refer to the published paper for details on the results of the study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719032/pdf/awaa279.pdf