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<p>Parkinson’s disease (PD) and related familial Parkinsonism are defined by motor dysfunction, but the specific upstream molecular causes of these clinical symptoms can vary widely. We hypothesize that these causes converge onto a limited number of core cellular pathways. To investigate this, we created a collection of 24 genetically well-controlled <i>Drosophila</i> models of familial forms of PD and related mono-genic forms of Parkinsonism. Using unbiased behavioral screening and machine learning we identify clusters of mutants that converge on (1) mitochondrial function; (2) retromer/vesicle trafficking and proteostasis/autophagy. Genes within each cluster have a similar genetic interaction profile and compounds that target specific molecular pathways ameliorate dopaminergic neuron dysfunction in a cluster-specific manner. Together, our data indicate that familial PD and related forms of Parkinsonism may fall into two broad functional groups, and may inform further work toward targeted biomarker discovery and therapeutic development.</p>

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Behavioral screening defines the molecular Parkinsonism-related subgroups in Drosophila

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月10日

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  • Natalie Kaempf,
  • Jorge S. Valadas,
  • Pieter Robberechts,
  • Nils Schoovaerts,
  • Roman Praschberger,
  • Antonio Ortega,
  • Eliana Nachman,
  • Lorenzo Ghezzi,
  • Ayse Kilic,
  • Dries Chabot,
  • Uli Pech,
  • Sabine Kuenen,
  • Sven Vilain,
  • El-Sayed Baz,
  • Jeevanjot Singh,
  • Jesse Davis,
  • Sha Liu,
  • Patrik Verstreken

摘要

Parkinson’s disease (PD) and related familial Parkinsonism are defined by motor dysfunction, but the specific upstream molecular causes of these clinical symptoms can vary widely. We hypothesize that these causes converge onto a limited number of core cellular pathways. To investigate this, we created a collection of 24 genetically well-controlled Drosophila models of familial forms of PD and related mono-genic forms of Parkinsonism. Using unbiased behavioral screening and machine learning we identify clusters of mutants that converge on (1) mitochondrial function; (2) retromer/vesicle trafficking and proteostasis/autophagy. Genes within each cluster have a similar genetic interaction profile and compounds that target specific molecular pathways ameliorate dopaminergic neuron dysfunction in a cluster-specific manner. Together, our data indicate that familial PD and related forms of Parkinsonism may fall into two broad functional groups, and may inform further work toward targeted biomarker discovery and therapeutic development.