| Parkinson's disease (PD) affects 1.5% of people over the age of 65. It is characterized by a progressive loss of motor movement, loss of substantia nigra (SN) dopamine neurons, and Lewy Body (LB) aggregates. Current therapies do not slow disease progression. A major limitation in the field of PD research is that though multiple transgenic mouse models have been created, no mammalian models robustly recapitulate disease phenotype. The role of alpha-synuclein has been well documented in PD. It is the major component of LBs, and mutations and gene duplications and triplications cause autosomal dominant PD. Rats are a better rodent model for neurobehavioral testing, drug testing, and multiple procedures including cannulation, electrophysiology and neuroimaging. Rats may also be more suitable models for neurological disease. We generated three bacterial artificial chromosome (BAC) transgenic alpha-synuclein rats (A53T, E46K, WT) and two LRRK2 rats (R1441G, G2019S), another prevalent PD gene. BACs contain large genomic DNA sequences which carry all the native structures and regulatory elements of a gene, and therefore show much more fidelity in spatio-temporal gene expression that is necessary to produce more accurate models of PD. Here, we discuss the characterization of A53T and E46K animal models. These animals express alpha-synuclein at levels 2-3 fold over control animals. Rats develop normally but have a decrease in DA metabolites and metabolite turnover at six months. Rats display diffuse granular alpha-synuclein pathology in axons and in the cytoplasm of neurons and glia. In A53T animals, asynuclein aggregates are SDS-resistant, cytoplasmic accumulation of alpha-synuclein colocalizes to tyrosine hydroxylase SN neurons, and appears to accumulate in the cytoplasm with age. Old A53T animals exhibit a decrease in weight compared with aged-matched controls and are behaviorally hyperactive. These results are consistent with early symptoms in previous animal models and PD patients. E46K animals are hypersensitive to rotenone treatment and acquire severe PD-like symptoms, weight loss, and reduced striatal tyrosine hydroxylase. These animals are the first transgenic rat models of PD, and model very early stages of the disease that can be exacerbated with additional stressors such as toxins, and perhaps future genetic crosses. |
