Parkinson’s disease (PD) is a neurodegenerative disorder with a high variability of age at onset, disease severity, and progression. This suggests that other factors, including genetic, environ-mental, or biological factors, are at play in PD. Loss of PINK1 causes a recessive form of PD and is typically fully penetrant; however, it features a wide range in disease onset, further supporting the existence of protective factors, endogenous or exogenous, to play a role. Loss of Pink1 in Drosophila melanogaster results in locomotion deficits, which are also observed in PINK1-related PD in humans. In flies, Pink1 deficiency induces defects in the ability to fly; none-theless, around ten percent of the mutant flies are still capable of flying, indicating that advanta-geous factors affecting penetrance also exist in flies. Here, we aimed to identify the mechanisms underlying this reduced penetrance in Pink1-deficient flies. We performed genetic screening in pink1-mutant flies to identify RNA expression alterations affecting the flying ability. The most important biological processes involved were transcription-al and translational activities, endoplasmic reticulum (ER) regulation, and flagellated movement and microtubule organization. We validated 2 ER-related proteins, zonda and windbeutel, to positively affect the flying ability of Pink1-deficient flies. Thus, our data suggest that these pro-cesses are involved in the reduced penetrance and that influencing them may be beneficial for Pink1 deficiency.

Parkinson’s disease (PD) is a neurodegenerative disorder with a high variability of age at onset, disease severity, and progression. This suggests that other factors, including genetic, environmental, or biological factors, are at play in PD. The loss of PINK1 causes a recessive form of PD and is typically fully penetrant; however, it features a wide range in disease onset, further supporting the existence of protective factors, endogenous or exogenous, to play a role. The loss of Pink1 in Drosophila melanogaster results in locomotion deficits, also observed in PINK1-related PD in humans. In flies, Pink1 deficiency induces defects in the ability to fly; nonetheless, around ten percent of the mutant flies are still capable of flying, indicating that advantageous factors affecting penetrance also exist in flies. Here, we aimed to identify the mechanisms underlying this reduced penetrance in Pink1-deficient flies. We performed genetic screening in pink1-mutant flies to identify RNA expression alterations affecting the flying ability. The most important biological processes involved were transcriptional and translational activities, endoplasmic reticulum (ER) regulation, and flagellated movement and microtubule organization. We validated two ER-related proteins, zonda and windbeutel, to positively affect the flying ability of Pink1-deficient flies. Thus, our data suggest that these processes are involved in the reduced penetrance and that influencing them may be beneficial for Pink1 deficiency.