@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 = {

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.

}, 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} } @article {84948, title = {Modulation of flight and feeding behaviours requires presynaptic IPRs in dopaminergic neurons.}, journal = {Elife}, volume = {9}, year = {2020}, month = {2020 Nov 06}, abstract = {

Innate behaviours, although robust and hard wired, rely on modulation of neuronal circuits, for eliciting an appropriate response according to internal states and external cues. flight is one such innate behaviour that is modulated by intracellular calcium release through inositol 1,4,5-trisphosphate receptors (IPRs). Cellular mechanism(s) by which IPRs modulate neuronal function for specific behaviours remain speculative, in vertebrates and invertebrates. To address this, we generated an inducible dominant negative form of the IPR (IPR). Flies with neuronal expression of IPR exhibit flight deficits. Expression of IPR helped identify key flight-modulating dopaminergic neurons with axonal projections in the mushroom body. Flies with attenuated IPRs in these presynaptic dopaminergic neurons exhibit shortened flight bouts and a disinterest in seeking food, accompanied by reduced excitability and dopamine release upon cholinergic stimulation. Our findings suggest that the same neural circuit modulates the drive for food search and for undertaking longer flight bouts.

}, issn = {2050-084X}, doi = {10.7554/eLife.62297}, author = {Sharma, Anamika and Hasan, Gaiti} } @article {83650, title = {Regulation of neuronal physiology by Ca2+ release through the IP3R}, journal = {Current Opinion in Physiology}, volume = {17}, year = {2020}, month = {10/10}, pages = {1-8}, abstract = {

Identification of mutations in the gene encoding the inositol 1,4,5-trisphosphate receptor Type 1 (IP3R1) as causative for Spinocerebellar Ataxia 15, 29 and Gillespie Syndrome emphasize the importance of understanding how the IP3R impacts neuronal function and physiology. Here we discuss how cellular changes due to IP3 mediated Ca2+release affect systemic physiology in Drosophila and mouse. The relevance of these findings to recently identified human neurological conditions are also discussed.

}, doi = {10.1016/j.cophys.2020.06.001}, author = {Hasan, Gaiti and Sharma, Anamika} }