Dopamine Release Defects Can Occur Before Neurodegeneration in PD

Although the death of dopaminergic neurons and reduced levels of striatal dopamine are often used to explain motor symptoms in patients with Parkinson disease (PD), dopamine deficits may not result from cell death alone, according to a review article published in Brain.

“A large body of work has demonstrated that in many models of PD, deficits in dopamine release from nigrostriatal neurons are present without, or before, neurodegeneration,” wrote corresponding author Stephanie J. Cragg, MA, DPhil, of the Oxford Parkinson’s Disease Centre and Department of Physiology, Anatomy, and Genetics at the University of Oxford in the United Kingdom, and coauthors.

The review article reports the evidence for dopamine release deficits prior to neurodegeneration from a large and emerging range of PD models as well as the mechanisms behind such deficits. It also presents key questions pertaining to dopamine release impairments that need to be addressed in future research.

“These defects frequently precede motor symptom onset and neuronal cell loss and seem to be now well established as a marker of PD prior to degeneration,” the authors wrote. “Much less well explored is whether, in turn, synaptic dysfunction is a marker that only heralds imminent cellular demise as an innocent bystander or whether this deficit has a detrimental impact on cell viability that contributes to the disease process, catalyzing disease progression through symptom onset or cell death.”

If the latter is found to be true, therapeutic strategies to restore axon function may offer hope not only for improvement in motor symptoms but also for neuroprotection against their future development, the authors wrote.

Reference

Cramb KML, Beccano-Kelly D, Cragg SJ, Wade-Martins R. Impaired dopamine release in Parkinson’s disease. Brain. 2023;146(8):3117-3132. doi:10.1093/brain/awad064