Rodent Models of Lewy Body Disease

Lewy body disease (LBD) is a progressive neurodegenerative disorder marked by the intracellular accumulation of misfolded α-synuclein into Lewy bodies and Lewy neurites. These inclusions, which also contain proteins like ubiquitin, neurofilaments, and synphilin-1, contribute to widespread neuronal dysfunction and death, particularly in dopaminergic and cholinergic pathways. The pathology follows a prion-like propagation of α-synuclein, with multiple contributing factors including genetic mutations, oxidative stress, mitochondrial dysfunction, impaired protein clearance systems, environmental toxins, and neuroinflammation. To study the complex mechanisms underlying LBD and identify potential therapeutic targets, rodent models are indispensable. This chapter provides a comprehensive overview of the pathological features of LBD and discusses both pharmacological and genetic rodent models used to investigate its pathogenesis. Pharmacological models involve administration of α-synuclein preformed fibrils (PFFs), mitochondrial toxins like rotenone and MPTP, environmental toxins such as paraquat and maneb, proteasome inhibitors (e.g., MG-132 and lactacystin), and ER stress inducers (tunicamycin, thapsigargin), all of which recapitulate key features of LBD. In parallel, genetic models include transgenic rodents overexpressing wild-type or mutant α-synuclein (such as the M83 and line 61 models), which allow for the study of age-dependent disease progression and synucleinopathy-related behavioral and cellular deficits. By integrating various modeling approaches, researchers can better simulate the multifactorial nature of LBD, gain deeper insights into the role of α-synuclein pathology, and evaluate novel therapeutic interventions. This chapter underscores the importance of model selection based on research objectives and highlights the contributions of rodent models in advancing our understanding of Lewy body-associated disorders.