
@article {161983,
	title = {Synergism of IP3R and Parkin mutants identifies mitochondrial stress as an early feature of Parkinson{\textquoteright}s Disease.},
	journal = {Dis Model Mech},
	year = {2025},
	month = {2025 Nov 14},
	abstract = {<p>Our understanding of mechanisms underlying familial Parkinson{\textquoteright}s Disease (PD) have benefitted from studies in Drosophila models of PD. However, in a majority of PD patients the disease occurs sporadically and cellular phenotypes that arise early in sporadic PD remain to be understood. A genetic predisposition, arising from mutations in pathways that impact dopaminergic neuron health could be one cause of sporadic PD. Here, we studied Drosophila with single copies of recessive IP3R gene (itpr) mutants placed in combination with a recessive null mutant for the parkin gene. Whereas individual mutants appear normal, in combination they synergise to exhibit flight motor deficits with a focus in a subset of central dopaminergic neurons. Surprisingly, mitophagy and mitochondrial Ca2+ are barely affected. Instead, flight motor deficits correlate with elevated levels of mitochondrial H2O2 and reducing H2O2 levels by genetic means restored mitochondrial function and flight to a significant extent. This study underlines the importance of mitochondrial oxidative stress as an early phenotype in PD and suggests that humans with recessive mutations in either pathway have a higher chance of developing sporadic PD.</p>
},
	keywords = {Calcium homeostasis; Dopaminergic neurons; Flight; Motor function; PPL1},
	issn = {1754-8411},
	doi = {10.1242/dmm.052146},
	author = {Dileep, Mrudula and Sharma, Anamika and Kasturacharya, Nandashree and Nizami, Syed Kavish and Manjila, Steffy and Bhan, Ashita and Hasan, Gaiti}
}
