Objective: To elucidate mechanisms of reduced penetrance in PINK1 deficiency.

Background: Loss of PINK1 causes recessive early-onset Parkinson’s disease (PD); however, how PINK1 deficiency results in PD remains elusive. A Drosophila melanogaster model exists for PINK1-related PD and resulting phenotypes are very well characterized. Expression of human wild type PINK1 in pink1 mutant flies can rescue these phenotypes, whereas expression of human mutant PINK1 does not, suggesting PINK1 function is evolutionarily conserved and that it is relevant to study PINK1 function and mechanisms in flies. Aside from mitochondrial defects, pink1 mutant flies also display difficulties in flying ability. Interestingly, 10% of the pink1 mutant flies are still capable of flying implicating a mechanism of reduced penetrance in this subset.

Methods: We performed a pilot study to test the existence of reduced penetrance in pink1 mutant flies. For this, we separated pink1 mutant flies derived from different parent pairs and tested their flying ability and ATP levels.

Results: We observed that flying ability of pink1 mutant flies originating from different parent pairs ranged from a complete lack of flying ability to 40% of flying ability. Levels of ATP reduction corresponded to the flying ability.

Conclusions: Our data suggest the existence of genetic modifiers that result in reduced penetrance of the phenotypes in pink1-deficient flies. Based on selected fly strains and using extremes of the phenotypes flying ability as well as of biochemical markers, we will identify the protective genetic modifiers using next-generation sequencing and RNA expression profiling. These data may provide new therapeutic targets as well as novel insights into the mechanisms of reduced penetrance that are present in PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/elucidating-mechanisms-of-endogenous-disease-protection-resulting-in-reduced-penetrance-in-pink1-deficiency/