1. Home
  2. News & Events
  3. News
  4. Synaptic Dopamine Storage Defect Uncovered as Key Mechanism in Parkinson’s Disease Neurons
News | 14/02/2026 | Research Spotlight

Synaptic Dopamine Storage Defect Uncovered as Key Mechanism in Parkinson’s Disease Neurons

In this study, dysfunctional vesicular dopamine packaging was uncovered as a central driver of dopamine oxidation and α-synuclein pathology in Parkinson’s disease (PD) neurons. Specifically, in PD-linked induced pluripotent stem cell (iPSC)-derived midbrain dopaminergic neurons lacking the PD-associated protein DJ-1, impaired vesicular monoamine transporter 2 (VMAT2) activity disrupts ATP-dependent dopamine packaging, triggers toxic dopamine oxidation and α-synuclein buildup – revealing a key mechanism in PD.

This is a summary of Heger et al. VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1–linked Parkinson’s neurons. Published in Science Advances (2026). DOI: 10.1126/sciadv.adz5645

The challenge

PD progressively destroys dopamine neurons in the brain, causing tremors, stiffness, and movement problems. Accumulation of α-synuclein to Lewy bodies and dopaminergic neuron degeneration are central hallmarks with the oxidation of dopamine – turning the neurotransmitter into toxic reactive species – emerging as a key pathological driver. However, the underlying causes of this pathological mechanism in human neurons were unclear.

Our approach

Using PD patient-derived and CRISPR-engineered iPSC midbrain dopaminergic neurons lacking the PD-associated gene DJ-1 (PARK7), we applied in-depth proteomics, state-of-the-art imaging, and ultrasensitive dopamine probes to dissect vesicular dopamine handling and homeostasis. Importantly, loss of DJ-1 function – associated with mitochondrial dysfunction and lack of ATP – is implicated in the more common sporadic form of PD beyond rare mutations.

Our findings

Dysfunction of vesicular monoamine transporter 2 (VMAT2) – the key transporter responsible for packaging dopamine into synaptic vesicles – impairs the ATP-dependent uptake of dopamine into synaptic vesicles, causing oxidation of dopamine, reduced vesicle availability, abnormal vesicle morphology, and α-synuclein accumulation. ATP supplementation fully restored vesicular function and alleviated dopamine-related pathologies in diseased neurons.

The implications

This ATP-sensitive VMAT2 mechanism links loss of DJ-1 and mitochondrial dysfunction to dopamine oxidation and synaptic failure, revealing enhanced dopamine sequestration as a promising disease-modifying strategy. The human iPSC platform opens avenues for targeted therapies preserving synaptic vesicle integrity in PD.

Creating SyNergies

This work integrates expertise across SyNergy labs specializing in iPSC disease modeling, advanced proteomics, and state-of-the-art imaging. Our study therefore highlights how interdisciplinary neurodegeneration research accelerates translation. Key contributing SyNergy researchers include Wolfgang Wurst, Stefan Lichtenthaler, Martina Schifferer and Christian Behrends, whose combined expertise bridges mechanism, modeling, and intervention.