Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Mutations and risk variants in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) are associated with late-onset Parkinson disease (PD).
• In vivo pathological evidence for CHCHD2 mutations in PD pathogenesis is currently lacking.
• Understanding the differential impact of pathogenic versus risk variants is crucial for targeted therapeutic strategies.

Purpose of the Study:

• To investigate the in vivo pathophysiological effects of pathogenic and risk variants of CHCHD2.
• To compare the severity of disease phenotypes caused by different CHCHD2 variants in a Drosophila model.
• To evaluate the neuroprotective potential of Ebselen in CHCHD2-associated Parkinsonism.

Main Methods:

• Generation of transgenic Drosophila models expressing pathogenic (p.Thr61Ile, p.Arg145Gln) and risk (p.Pro2Leu) CHCHD2 variants.
• Assessment of locomotor function, dopaminergic neuron survival, lifespan, mitochondrial function, oxidative stress, and synaptic transmission.
• Evaluation of rotenone exacerbation and Ebselen treatment effects on disease phenotypes.

Main Results:

• All CHCHD2 variants induced locomotor dysfunction, dopaminergic neuron degeneration, reduced lifespan, mitochondrial dysfunction, oxidative stress, and impaired synaptic transmission.
• Pathogenic variants (p.Thr61Ile and p.Arg145Gln) exhibited more severe motor deficits, neuronal loss, and oxidative stress than the risk variant (p.Pro2Leu).
• Ebselen treatment ameliorated motor function, showing greater efficacy in mutant versus risk variant models, suggesting differential drug responses.

Conclusions:

• This study provides the first in vivo evidence demonstrating the pathological effects of CHCHD2 mutations in a Drosophila model of Parkinson disease.
• Pathogenic CHCHD2 variants induce more severe phenotypes than risk variants, highlighting distinct disease contributions.
• Ebselen shows potential as a neuroprotective agent for individuals carrying CHCHD2 mutations relevant to Parkinson disease.