Lewy body diseases (LBD) are complex neurodegenerative conditions that originate from an accumulation of misfolded alpha-synuclein (α-syn) often association with other proteins such as Amyloid β (Aβ), Tau, and TAR-DNA-binding protein. However, the nature of this association is poorly understood. To investigate the complex pathology of LBD, we constructed 2 novel transgenic overexpressing C. elegans models using human genes (α-synA53T;Taupro-agg and α-synA53T;Aβ1-42;Taupro-agg ). We then investigated the molecular, physiologic, and behavioral alterations of these and previously produced models. These nematode LBD models demonstrate molecular and behavior impairments including uncoordinated movement, egg-laying deficits, altered serotonin and cholinergic signaling, memory and posture deficits, as well as dopaminergic neuron damage and loss. Expression levels of total and aggregated α-syn protein were increased in α-synA53T;Aβ1-42 but decreased in α-synA53T;Taupro-agg compared to α-synA53T transgenic animals. These alterations were similar at the mRNA level suggesting a pre-transcriptional mechanism. miRNA-seq revealed that cel-miR-1018 was upregulated in LBD models including in α-synA53T, α-synA53T;Aβ1-42, and α-synA53T;Taupro-agg compared with WT. The predicted miRNA targets include atp-2, cox-4 and F58F12.1 suggesting the regulation of oxidative phosphorylation. Our results provide evidence of interactions between different pathological proteins and alterations in specific miRNAs that may further exacerbate or ameliorate LBD pathology. Funding: This study was funded by the Faculty of Science, University of Macau MYRG2020-00213-FHS.