# Endoplasmic Reticulum Proteins Impact Penetrance in a Pink1-Mutant Drosophila Model

## TL;DR

This study explores how ER proteins affect the severity of a Parkinson's-related mutation in fruit flies, revealing potential protective mechanisms.

## Contribution

The study identifies ER-related proteins that influence the penetrance of Pink1 deficiency in Drosophila.

## Key findings

- Genetic screening revealed transcriptional and translational activities, ER regulation, and microtubule organization as key processes.
- ER proteins zonda and windbeutel were validated to improve flying ability in Pink1-deficient flies.
- These findings suggest that ER processes may reduce disease penetrance in Pink1 deficiency.

## Abstract

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.