2026/01/01 by Dina Mikimoto · 1 voice
Medicine · Neuroscience · #Parkinson's Disease Mechanisms and Treatments #Autophagy in Disease and Therapy #Nuclear Receptors and Signaling
paper · doi:10.1242/dmm.052818
openalex publication_date 2026/01/01 · openalex created_date 2026/01/22 · openalex updated_date 2026/05/06
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterised by loss of dopaminergic neurons from the substantia nigra pars compacta, a region of the human brain involved in motor control. PD can be familial (arising from inherited genetic mutation) or sporadic (resulting from a multifactorial combination of ageing, environmental exposures and genetic susceptibility). Neuronal function depends on mitochondrial energy production to maintain membrane potential and neurotransmission, but these processes can cause mitochondrial damage through the generation of reactive oxygen species. In healthy cells, bioenergetically compromised mitochondria are removed from the cells (mitophagy), which involves the PINK1/parkin pathway. Mitochondrial functioning additionally relies on Ca2+, which is required for several mitochondrial dehydrogenases. Disruption of either mitophagy or Ca2+ signalling has been implicated in PD pathology.In this study, Mrudula Dileep, Anamika Sharma, Gaiti Hasan and their colleagues investigated whether sporadic PD could arise from convergent toxicity caused by compromised PINK1/parkin and intracellular Ca2+ signalling pathways in dopaminergic neurons. The authors performed experiments using Drosophila carrying mutations in the genes encoding Parkin and the Inositol 1,4,5-trisphosphate receptor (an intracellular Ca2+ channel located on the endoplasmic reticulum), identifying a strong interaction between the encoding genes, which impaired the function of dopaminergic neurons. Single-copy mutations in either gene alone had minimal impact on mitophagy and neuronal Ca2+ release. However, combining both mutations produced a cumulative deficit that reduced mitochondrial energy production during neuronal depolarisation and led to toxic accumulation of H2O2. The authors further showed that overexpression of the antioxidant catalase partially compensated for this energy deficit by restoring the ATP/ADP ratio. Catalase overexpression rescued neuronal function, likely by removing excess H2O2 produced through dopamine oxidation and an overactive electron transport chain.Together, these findings identify oxidative stress as an early driver of dopaminergic neuron dysfunction in PD and suggest that sustained, uncontrolled oxidative stress contributes to later neurodegenerative phenotypes. The study further implies that individuals carrying recessive mutations affecting mitophagy or intracellular Ca2+ signalling could be at increased risk of developing sporadic PD.