Abstract:
Mitochondrial dysfunction is well-established in Parkinson’s disease (PD); however, its
dysfunctions associating with cell organelle connectivity remain unknown. We aimed to establish the
crucial cytosolic protein involved in organelle connectivity between mitochondria and the endopalmic
reticulum (ER) through a computational approach by constructing an organelle protein network to
extract functional clusters presenting the crucial PD protein connecting organelles. Then, we assessed
the influence of anti-parkinsonism drugs (n = 35) on the crucial protein through molecular docking
and molecular dynamic simulation and further validated its gene expression in PD participants under,
istradefylline (n = 25) and amantadine (n = 25) treatment. Based on our investigation, D-aspartate
oxidase (DDO )protein was found to be the critical that connects both mitochondria and the ER.
Further, molecular docking showed that istradefylline has a high affinity (−9.073 kcal/mol) against
DDO protein, which may disrupt mitochondrial-ER connectivity. While amantadine (−4.53 kcal/mol)
shows negligible effects against DDO that contribute to conformational changes in drug binding,
Successively, DDO gene expression was downregulated in istradefylline-treated PD participants,
which elucidated the likelihood of an istradefylline off-target mechanism. Overall, our findings
illuminate the off-target effects of anti-parkinsonism medications on DDO protein, enabling the
recommendation of off-target-free PD treatments
