Parkinson’s disease has long been understood as the product of a complicated interplay between inherited susceptibility and environmental stress. Yet for many affected families, genetic testing still fails to reveal why the disease develops. A new study published in Science Bulletin now identifies biallelic variants in the H6PD gene as a cause of an autosomal recessive form of Parkinson’s disease, linking the mutations to a previously underappreciated cellular failure: the breakdown of the physical and functional communication network between the endoplasmic reticulum and mitochondria.
The discovery emerged from a large-scale investigation that combined family-based genetic analysis with population-level sequencing. Researchers from Central South University began by studying families affected by Parkinson’s disease, using homozygosity mapping and next-generation sequencing to search for regions of the genome shared by patients. They then examined data from 6,233 people with Parkinson’s disease and 7,301 control individuals. Across this extensive dataset, the team identified 13 biallelic H6PD variants in eight unrelated probands, providing genetic evidence that both altered copies of the gene can drive disease.
The H6PD gene encodes hexose-6-phosphate dehydrogenase, an enzyme located in the endoplasmic reticulum, a membrane-bound organelle responsible for protein processing, lipid metabolism and calcium regulation. H6PD also contributes to the production of reducing equivalents that help maintain the organelle’s redox environment. When both copies of H6PD are defective, this biochemical support system is compromised. The result is increased oxidative stress within the endoplasmic reticulum, exposing cells to abnormal levels of reactive oxygen species and undermining the stability of neighboring cellular structures.
The researchers focused on mitochondria-associated membranes, or MAMs, specialized contact sites where the endoplasmic reticulum meets mitochondria. Although the two organelles remain physically distinct, MAMs allow them to exchange calcium, lipids and signaling molecules while coordinating energy production, stress responses and mitochondrial quality control. The study found that H6PD deficiency damages the structure of these contact sites. In effect, the molecular bridge connecting the two organelles becomes unstable, interrupting the communication required to keep mitochondria healthy.
This disruption sets off a chain of events particularly dangerous for dopaminergic neurons, the nerve cells lost in Parkinson’s disease. Impaired MAM integrity was associated with an accumulation of reactive oxygen species, mitochondrial dysfunction and reduced activity of the PINK1-Parkin mitophagy pathway. Mitophagy is the cellular process responsible for identifying and removing damaged mitochondria. Under normal conditions, PINK1 and Parkin label defective mitochondria for disposal. When this pathway is suppressed, damaged mitochondria accumulate, producing further oxidative stress and placing neurons under sustained metabolic pressure.
Dopaminergic neurons are especially vulnerable because they have high energy demands and extensive cellular projections that must be maintained over long distances. Their dependence on efficient mitochondrial function makes them sensitive to failures in energy production and quality control. According to the study, the combination of oxidative stress, disrupted ER-mitochondria contacts and defective mitophagy ultimately promotes the degeneration of these neurons, creating a direct mechanistic link between H6PD mutations and Parkinsonian pathology.
The team tested this mechanism in several experimental systems. In fruit flies, loss of the H6PD ortholog, known as Zw, caused the depletion of dopaminergic neurons, reduced dopamine levels, impaired locomotion and a shortened lifespan. The researchers then introduced a normal human H6PD gene into the mutant flies. This intervention substantially rescued the neurological, behavioral and survival defects, demonstrating that the observed phenotypes were specifically related to the loss of H6PD function rather than to unrelated genetic abnormalities.
Additional evidence came from mice. Using stereotactic delivery of an adeno-associated virus carrying short hairpin RNA, the researchers reduced H6pd expression in the brain. When these animals were exposed to MPTP, a neurotoxin widely used to model Parkinson’s disease, H6PD deficiency intensified dopaminergic neuronal loss and worsened mitochondrial abnormalities. The result suggests that reduced H6PD activity may not only initiate cellular stress but also increase the brain’s vulnerability to additional environmental or chemical insults.
Together, the findings establish a pathogenic sequence that begins with inherited H6PD variation and proceeds through endoplasmic reticulum oxidative stress, MAM disruption and mitophagy failure before culminating in dopaminergic neurodegeneration. The work also broadens the genetic landscape of Parkinson’s disease by showing that defects in organelle communication can be as important as mutations in proteins directly involved in mitochondrial quality control. While the findings do not immediately produce a treatment, they point toward possible strategies aimed at restoring ER-mitochondria contacts, reducing oxidative stress or reactivating PINK1-Parkin-dependent mitophagy. For families carrying biallelic H6PD variants, the discovery may eventually support more precise diagnosis and genetically informed care.
Subject of Research: Biallelic H6PD variants as a cause of autosomal recessive Parkinson’s disease, and their effects on ER-mitochondria contact sites, oxidative stress and mitophagy.
Article Title: Biallelic H6PD Variants Cause Parkinson’s Disease Through Disruption of ER-Mitochondria Contact Sites
Web References: https://doi.org/10.1016/j.scib.2026.07.038
References: Science Bulletin, DOI: 10.1016/j.scib.2026.07.038
Image Credits: © Science Bulletin
Keywords: Parkinson’s disease, H6PD, autosomal recessive inheritance, mitochondria-associated membranes, endoplasmic reticulum, mitochondrial dysfunction, mitophagy, PINK1-Parkin pathway, oxidative stress, dopaminergic neurons
