Lewy body diseases (LBD) comprise a group of complex neurodegenerative conditions originating from accumulation of misfolded alpha-synuclein (&#
x3b1;-syn) in the form of Lewy bodies. LBD pathologies are characterized by &#
x3b1;-syn deposition in association with other proteins such as Amyloid &#
x3b2; (A&#
x3b2;), Tau, and TAR-DNA-binding protein. To investigate the complex interactions of these proteins, we constructed 2 novel transgenic overexpressing (OE) C. elegans strains (&#
x3b1;-syn<sub>A53T</sub>;Tau<sub>pro-agg</sub> (OE) and &#
x3b1;-syn<sub>A53T</sub>;A&#
x3b2;1-42;Tau<sub>pro-agg</sub> (OE)) and compared them with previously established Parkinson's, Alzheimer's, and Lewy Body Dementia disease models. The LBD models presented here demonstrate impairments including uncoordinated movement, egg-laying deficits, altered serotonergic and cholinergic signaling, memory and posture deficits, as well as dopaminergic neuron damage and loss. Expression levels of total and prone to aggregation &#
x3b1;-syn protein were increased in &#
x3b1;-syn<sub>A53T</sub>;A&#
x3b2;<sub>1-42</sub> but decreased in &#
x3b1;-syn<sub>A53T</sub>;Tau<sub>pro-agg</sub> animals when compared to &#
x3b1;-syn<sub>A53T</sub> animals suggesting protein interactions. These alterations were also observed at the mRNA level suggesting a pre-transcriptional mechanism. miRNA-seq revealed that cel-miR-1018 was upregulated in LBD models &#
x3b1;-syn<sub>A53T</sub>, &#
x3b1;-syn<sub>A53T</sub>;A&#
x3b2;<sub>1-42</sub>, and &#
x3b1;-syn<sub>A53T</sub>;Tau<sub>pro-agg</sub> compared with WT. cel-miR-58c was upregulated in &#
x3b1;-syn<sub>A53T</sub>;Tau<sub>pro-agg</sub> but downregulated in &#
x3b1;-syn<sub>A53T</sub> and &#
x3b1;-syn<sub>A53T</sub>;A&#
x3b2;<sub>1-42</sub> compared with WT. cel-miR-41-3p and cel-miR-355-5p were significantly downregulated in 3 LBD models. Our results obtained in a model organism provide evidence of interactions between different pathological proteins and alterations in specific miRNAs that may further exacerbate or ameliorate LBD pathology.