Environmental toxins trigger PD-like progression via increased alpha-synuclein release from enteric neurons in mice

Abstract

Pathological studies on Parkinson's disease (PD) patients suggest that PD pathology progresses from the enteric nervous system (ENS) and the olfactory bulb into the central nervous system. We have previously shown that environmental toxins acting locally on the ENS mimic this PD-like pathology progression pattern in mice. Here, we show for the first time that the resection of the autonomic nerves stops this progression. Moreover, our results show that an environmental toxin (i.e. rotenone) promotes the release of alpha-synuclein by enteric neurons and that released enteric alpha-synuclein is up-taken by presynaptic sympathetic neurites and retrogradely transported to the soma, where it accumulates. These results strongly suggest that pesticides can initiate the progression of PD pathology and that this progression is based on the transneuronal and retrograde axonal transport of alpha-synuclein. If confirmed in patients, this study would have crucial implications in the strategies used to prevent and treat PD.

α-Synuclein in gut endocrine cells and its implications for Parkinson’s disease

“…exposure to the environmental toxin rotenone (22) as well as following direct injection of adenoassociated viral vectors overexpressing human α-synuclein into the vagus nerve (23). A route from intrinsic enteric neurons to the vagus nerve is supported by the observation that both myenteric neurons and preganglionic vagal nerves express α-synuclein (24).…”

Pesticides and Parkinson’s Disease: is It in Your genes?

“…Pan-Montojo et al tested this hypothesis in an eloquent series of experiments that demonstrated the ability of small amounts of rotenone delivered to the enteric nerves to initiate α-syn pathology in mice. Strikingly, resection of the autonomic nerves prevented its spread to the CNS [20].…”

Products of the Parkinson’s-disease related glyoxalase DJ-1, D-lactate and glycolate, support mitochondrial membrane potential and neuronal survival

“…DJ-1 is reported to exert its neuroprotective function in mitochondria (Junn et al, 2009). Many genes involved in Parkinson's disease, among them DJ-1, have been linked to alterations in mitochondrial structure and function and an enhanced sensitivity to mitochondrial toxins like Complex-I inhibitors (Clark et al, 2006;Park et al, 2006;Irrcher et al, 2010;Kamp et al, 2010;Sai et al, 2012;Wang et al, 2012;Burchell et al, 2013). Thus we decided to test the structure and function of mitochondria in the absence of DJ-1 (ΔΔdjr) or complete glyoxalase activity (Δglo), as revealed by staining with MitoTracker CMXRos (Figure 2A) (Pendergrass et al, 2004).…”

“…http://dx.doi.org/10.1101/006916 doi: bioRxiv preprint first posted online Jul. 4, 2014; mitochondria are strongly linked to the appearance of Parkinson's disease (Song et al, 2004;Freire and Koifman, 2012) and impairment of the mitochondrial function is a common feature of both idiopathic and genetic Parkinson's disease (Schapira et al, 1989;Clark et al, 2006;Park et al, 2006;Irrcher et al, 2010;Kamp et al, 2010;Pan-Montojo et al, 2012;Wang et al, 2012;Braidy et al, 2013;Burchell et al, 2013). Our discovery that the production of molecules from endogenous enzymatic pathways can protect neurons, offers a potential therapeutic direction that could include preventive strategies.…”