A phenotypic model recapitulating the neuropathology of Parkinson's disease

Abstract

This study was undertaken to develop a phenotypic model recapitulating the neuropathology of Parkinson's disease (PD). Such a model would show loss of dopamine in the basal ganglia, appearance of Lewy bodies, and the early stages of motor dysfunction. The model was developed by subcutaneously injecting biodegradable microspheres of rotenone, a complex I inhibitor in 8–9 month old, ovariectomized Long–Evans rats. Animals were observed for changes in body weight and motor activity. At the end of 11–12 weeks animals were euthanized and the brains examined for histopathological changes. Rotenone treated animals gain weight and appear normal and healthy as compared to controls but showed modest hypokinesia around 5–6 weeks posttreatment. Animals showed loss of dopaminergic (DA) neurons and the appearance of putative Lewy bodies in the substantia nigra. Neuroinflammation and oxidative stress were evidenced by the appearance of activated microglia, iron precipitates, and 8-oxo-2′-deoxyguanosine a major product of DNA oxidation. The dorsal striatum, the projection site of midbrain DA neurons, showed a significant reduction in tyrosine hydroxylase immunostaining, together with an increase in reactive astrocytes, an early sign of DA nerve terminal damage. Levels of vesicular monoamine transporter 2 (VMAT2) were significantly reduced in the dorsal striatum; however, there was an unexpected increase in dopamine transporter (DAT) levels. Old, ovariectomized females treated with rotenone microspheres present with normal weight gain and good health but a modest hypokinesia. Accompanying this behavioral phenotype are a constellation of neuropathologies characteristic of PD that include loss of DA neurons, microglia activation, oxidative damage to nuclear DNA, iron deposition, and appearance of putative Lewy bodies. This phenotypic model recapitulating the neuropathology of Parkinson's disease could provide insight into early mechanisms of pathogenesis and could aid in the identification of biomarkers to identify patients in early stage, PD.

Genetic aberrations in iPSCs are introduced by a transient G1/S cell cycle checkpoint deficiency

“…When we conducted ROS induction at days 2-3 of iPSC generation using either IR or rotenone, which is an 8-oxoG producer 44 , we obtained iPSCs harboring a larger number of point mutations than the control iPSC clones (Fig. 8b, c).…”

Forced exercise activates the NrF2 pathway in the striatum and ameliorates motor and behavioral manifestations of Parkinson's disease in rotenone-treated rats

“…This allows for accumulation and overproduction of reactive oxygen species which eventually lead to cell damage. (3,4) Chronic rotenone exposure in rats causes both neuropathological ndings and behavioral symptoms of PD (5). The rotenone model mimics the gradual progression of PD as observed in humans.…”

Parkinson's Disease and Restless Legs Syndrome

“…PD is a chronic disease progressing slowly after onset over the life span, while it is unknown if RLS is a progressive condition or expressing different phenotypes during advancing age. The pathological hallmark of PD is synuclein aggregation to form Lewy neuritis and Lewy bodies associated with the destruction of dopaminergic DA neurons in the substantia nigra pars compacta region [14]. The precise pathophysiology of RLS is not known, but a decrease of brain iron seems to play an important role [1].…”