While experts know that Parkinson’s disease (PD) is driven by a complex mix of genetic and environmental factors, the specific genetic causes for many patients remain unknown. In a breakthrough study, researchers have identified H6PD (hexose-6-phosphate dehydrogenase) as a novel causative gene for Parkinson’s disease. This study establishes that biallelic variants in H6PD gene cause an autosomal recessive form of PD, pinpointing a defect in the structural connection between the endoplasmic reticulum (ER) and mitochondria as the root of the neurodegeneration.
“Our team has long been dedicated to uncovering genetic causes of Parkinson’s disease,” explains Prof. Zhenhua Liu, from the Neurology department, Xiangya Hospital, Central South University, and the corresponding author of the study. “We successfully identified a novel gene for autosomal recessive Parkinson’s disease using genetic analysis. But simply finding the gene was not enough—we were driven to uncover the molecular mechanism to understand exactly how this genetic mutations lead to the disease.”
Massive Genomic Datasets Pinpoint a New Recessive Gene
To identify novel genetic factor for PD, the team conducted a comprehensive genetic screen using massive genomic datasets. The investigation began with a detailed analysis of PD families, where they combined homozygosity mapping with next-generation sequencing to identify candidate genes. They then validated and expanded these findings across broader populations, analyzing genomic data from 6233 PD patients and 7301 controls. This rigorous approach identified 13 biallelic H6PD variants across eight probands. H6PD is an enzyme located in the endoplasmic reticulum that plays a vital role in maintaining cellular redox balance. The discovery of these biallelic variants—where both copies of the gene inherited from parents are mutated—confirms H6PD as a new autosomal recessive causative gene for PD, providing a definitive genetic diagnosis for these families.
Genetic Defect Collapses the "Bridge" Between ER and Mitochondria
The study highlights a critical pathological mechanism triggered by this genetic loss. The researchers discovered that H6PD deficiency causes structural damage to the Mitochondria-Associated Membranes (MAMs)—the critical contact sites where the ER and mitochondria physically connect.
“It acts like a collapse of the cellular bridge between two vital compartments,” explains Prof. Jieqiong Tan, from School of Life Sciences, Central South University and the co-corresponding author of the study. “The loss of H6PD disrupts the integrity of these MAMs. This structural breakdown triggers a chain reaction: massive accumulation of reactive oxygen species (ROS), mitochondrial dysfunction, and the suppression of PINK1-Parkin-dependent mitophagy.”
The team revealed that this “quality control” failure leads to the accumulation of damaged mitochondria, ultimately inducing the death of dopaminergic neurons.
Validation Across Models: A Rescuable Phenotype
The researchers validated the pathogenicity of these variants through extensive functional studies. In fruit fly models, knocking out the H6PD homolog led to the loss of dopaminergic neurons, reduced dopamine levels, locomotor deficits, and shortened lifespan. Crucially, expressing the human wild-type H6PD gene was able to significantly rescue these pathological and behavioral phenotypes, confirming the gene’s vital role. Besides, in a mouse model, knocking down H6pd via stereotactic injection of AAV-shRNA significantly aggravated MPTP-induced neuronal loss and mitochondrial pathological changes. This study successfully establishes a complete pathological chain: "Genetic Variation ( H6PD ) - Structural Damage (MAMs) - Mitophagy Failure."
“Right now, treatments for PD focus primarily on managing symptoms,” Prof. Liu says. “Our findings provide the first direct evidence that H6PD is a disease-causing gene and that the ER-mitochondria connection is the weak spot. For patients carrying these variants, restoring this communication could serve as potential targeted therapeutic strategies.”
About the study
The study relied on extensive whole-exome and whole-genome sequencing datasets. Functional validation of the identified variants was conducted through a multidisciplinary approach, utilizing advanced imaging and metabolic flux analysis to assess mitochondrial function and redox status in cell lines, Drosophila, and mouse models. The research was conducted in close cooperation between the genetic, neurological, and neurobiological research departments at Central South University, aiming to translate fundamental genetic discoveries into potential clinical breakthroughs for neurodegenerative diseases.
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Data/statistical analysis