Integrated Behavioral and Proteomic Characterization of MPP+-Induced Early Neurodegeneration and Parkinsonism in Zebrafish Larvae

TL;DR

This study uses zebrafish larvae to model early Parkinson's-like symptoms and identifies key molecular changes linked to neurodegeneration.

Contribution

The study introduces an integrated behavioral and proteomic approach to model early Parkinsonism in zebrafish larvae.

Findings

MPP+ exposure in zebrafish larvae caused Parkinsonian-like motor dysfunction, including reduced movement and light-evoked responses.

Proteomic analysis identified 40 differentially expressed proteins linked to mitochondrial dysfunction, oxidative stress, and synaptic impairment.

Key Parkinsonism-related proteins like DJ-1 and SDHA showed coordinated dysregulation, suggesting early-stage neurodegenerative pathways.

Abstract

Zebrafish (Danio rerio) combine accessible behavioral phenotypes with conserved neurochemical pathways and molecular features of vertebrate brain function, positioning them as a powerful model for investigating early neurodegenerative processes and screening neuroprotective strategies. In this context, integrated behavioral and proteomic analyses provide valuable insights into the initial pathophysiological events shared by conditions such as Parkinson’s disease and related disorders—including mitochondrial dysfunction, oxidative stress, and synaptic impairment—which emerge before overt neuronal loss and offer a crucial window to understand disease progression and evaluate therapeutic candidates prior to irreversible damage. To investigate this early window of dysfunction, zebrafish larvae were exposed to 500 μM 1-methyl-4-phenylpyridinium (MPP+) from 1 to 5 days post-fertilization and evaluated through integrated behavioral and label-free proteomic analyses. MPP+-treated larvae exhibited hypokinesia, characterized by significantly reduced total distance traveled, fewer movement bursts, prolonged immobility, and a near-complete absence of light-evoked responses—mirroring features of early Parkinsonian-like motor dysfunction. Label-free proteomic profiling revealed 40 differentially expressed proteins related to mitochondrial metabolism, redox regulation, proteasomal activity, and synaptic organization. Enrichment analysis indicated broad molecular alterations, including pathways such as mitochondrial translation and vesicle-mediated transport. A focused subset of Parkinsonism-related proteins—such as DJ-1 (PARK7), succinate dehydrogenase (SDHA), and multiple 26S proteasome subunits—exhibited coordinated dysregulation, as visualized through protein–protein interaction mapping. The upregulation of proteasome components and antioxidant proteins suggests an early-stage stress response, while the downregulation of mitochondrial enzymes and synaptic regulators reflects canonical PD-related neurodegeneration. Together, these findings provide a comprehensive functional and molecular characterization of MPP+-induced neurotoxicity in zebrafish larvae, supporting its use as a relevant in vivo system to investigate early-stage Parkinson’s disease mechanisms and shared neurodegenerative pathways, as well as for screening candidate therapeutics in a developmentally responsive context.

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