From dosage alteration to amplification strategies: mechanistically defined alpha-synuclein mouse models for Parkinson’s disease therapy development

A major challenge for identifying a disease-modifying cure for Parkinson’s disease (PD) is creating models resembling key features of the disease including resting tremor, bradykinesia, muscle rigidity and gait disturbances. In addition, PD patients often develop cognitive symptoms that are associated with pathology in neocortical areas. Initially, PD rodent models were generated primarily by chemical neurotoxins that induce an acute loss of dopaminergic neurons. Upon discovery of familial-PD-linked genetic mutations in the SNCA gene—encoding α-synuclein (αS)—mice carrying these mutations provided deeper insight into the pathologic role of this synaptic protein throughout the brain. αS transgenic mouse models stand out for their ability to develop intraneuronal lesions that are rich in αS phospho-serine 129, a histopathological signature of the human PD brain. Recent advances in αS protein biochemistry led to the generation of mice carrying strategic amplifications of familial-PD-linked αS mutants, resulting in more pronounced neurodegeneration and progressive phenotype development. Here we review advances of αS transgenic mouse model development with a focus on strategic mutations that may have greater potential for identifying underlying disease mechanisms than classical single-mutant and wild-type αS overexpressing mice. We also present how the mice are currently used in testing drug efficacy and target engagement for PD drug discovery and outline strategies for utilizing such mice in basic and translational research.