Dietary Serine Prevents the Parkinsonian‐Like Dysfunctions Induced by Subthreshold Doses of Paraquat and Lectin

An intriguing theory suggests that ingested environmental toxins are triggering factors in the development of idiopathic Parkinson's disease (iPD). Accordingly, misfolded α‐synuclein, i.e. the histological hallmark of PD, is first found in myenteric neurons of the gastrointestinal tract, and, upon PD progression, in vagal pathways and in the central nervous system, including the substantia nigra pars compacta. Experimental PD can be induced by repeated exposure to high doses of paraquat, however in humans iPD is unlikely to result from exposure to high doses of a single agent administered over a short period of time; iPD may rather be the consequence of repeated exposures to low doses of toxins, or a combination of toxins, whose pathogenicity is enhanced by external factors. Here we use a combination of in vitro and in vivo techniques to test the hypotheses that: i) subthreshold doses of dietary lectins+paraquat induce the formation of misfolded α‐synuclein fibrils and induces PD‐like motor dysfunctions; and, ii) dietary serine supplementation prevents/attenuates the formation of misfolded α‐synuclein fibrils in lectin+paraquat experimental groups. In vitro : a solution containing α‐synuclein (35μM), paraquat (100μM) and/or lectin from P. sativum (0.0025%) and/or serine (0.25%) was incubated with constant shaking. Samples were collected every hour up to 48hrs, and the formation of fibrils was assessed by fluoroscopy. In vivo: male SD rats were gavaged daily for 7 days with paraquat (1mg/kg;1P) and/or lectin (0.05%; L), or paraquat (5mg/kg; 5P) alone. Another group of rats was fed a serine‐supplemented diet in addition to the oral gavage (1P+L+Serine, or 5P+Serine). The stepping test was performed weekly up to 3 weeks after the end of the treatment to assess the Parkinsonian motor phenotype. After the last motor test, rats were euthanized, the gastrointestinal tract extracted and the neurochemical phenotype of myenteric neurons of stomach, duodenum and colon assessed. The time to half‐maximum fibril formation (t½) in the P or L groups alone was ~20hr, whereas it was reduced significantly to ~12hrs in the P+L group, indicating a synergistic effect. When serine was added to the solution, t½ was increased to ~43hrs suggesting a significant attenuation of the rate of fibril formation. Motor functions were significantly reduced in rats which received 5P (−40%; N=3) or P1+L (−28%; N=4)(P<0.05 vs control, L or P1) but not rats that received L (N=5) or P1 (N=4) alone. Dietary serine supplementation of rats in the P1+L (N=3) and P5 (N=3) prevented the impairment of the motor performance, suggesting a neuroprotective effect of serine. Immunohistochemical analysis indicated that lectins were co‐localized with NOS‐ and NeuN immunoreactive neurons, indicating that they were up‐taken by motor as well as sensory neurons. Misfolded α‐synuclein and lectins were also found in ~50% of myenteric neurons. These data indicate that subthreshold doses of dietary lectins+paraquat favor the formation of misfolded α‐synuclein fibrils in myenteric neurons and induce PD‐like motor dysfunctions, and dietary serine supplementation prevents or attenuates the formation of misfolded α‐synuclein fibrils and the PD‐like motor dysfunctions. Support or Funding Information NIH DK 55530