A Novel Autosomal Dominant Parkinsonism/Cerebellar Ataxia Syndrome Caused by Cysteinyl-tRNA Synthetase Mutation

Background

Recently, a Chinese research team discovered a new pathogenic gene for a rare neurodegenerative disease that presents as a combination of Parkinson’s disease and cerebellar ataxia symptoms, which does not fit the description of known neurodegenerative diseases. The study showed that a mutation in the glutaminyl-tRNA synthetase (CARS) gene is the pathological cause of the syndrome. This research reveals a new pathogenic mechanism for neurodegenerative diseases, which is significant for understanding pathology and developing future treatment strategies.

Research Origin

The study was jointly completed by scholars Liu Hankui, Hao Honglin, You Hui, and others. The research team comes from institutions including BGI-Shenzhen, Peking Union Medical College Hospital, University of Science and Technology of China, Institute of Imaging, Chinese Academy of Medical Sciences, and Peking University Third Hospital. The research findings were published in the journal “Neuroscience Bulletin”.

Research Methods

The study included 90 family members who underwent physical examinations, neurological assessments, and international rating scales to evaluate ataxia, Parkinson’s symptoms, and cognitive function. Seven sequences of cranial magnetic resonance imaging were used to explore brain degenerative changes. Whole-genome sequencing and linkage analysis were used to search for abnormal repeat expansion sites, pathogenic variants in known cerebellar ataxia-related genes, and rare new mutations. A rare CARS gene missense mutation was verified by Sanger sequencing, and the aminoacylation activity of the mutant CARS was detected by spectrophotometry.

Main Findings

• Core features of late-onset cerebellar ataxia, Parkinson’s symptoms, and pyramidal signs were observed in nine affected family members.
• Magnetic resonance imaging showed cerebellar/pontine atrophy and decreased local blood flow in the midbrain basal ganglia region, suggesting neurodegenerative changes.
• Whole-genome sequencing identified a novel pathogenic heterozygous mutation (E795V) in the CARS gene, without known repeat expansions or pathogenic gene point mutations.
• Compared to the wild type, the CARS mutation resulted in approximately 20% reduction in aminoacylation activity in protein synthesis.

Research Significance

This study is the first to confirm that a CARS gene missense mutation leads to Parkinson’s disease and cerebellar ataxia syndrome, providing a new perspective for the etiology of neurodegenerative diseases.

Special Findings

• The study described the exact link between CARS gene mutation and the occurrence of specific neurodegenerative symptoms.
• The CARS gene null allele is a new variant in the Chinese population and shows a rare distribution in the Han population.
• The research provides new insights into the human disease spectrum and enhances our understanding of the genetic architecture of aminoacyl tRNA synthetase-related neurological diseases.

Research Limitations and Future Prospects

More research is needed to determine the distribution of CARS mutations globally and their clinical manifestations in different ethnicities, as well as their specific impact on disease progression. Future research may be able to develop treatments targeting this specific gene mutation.