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

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 PDThis work was supported by the Fritz-Thyssen Foundation, theGerman Parkinson’s disease Society and by Amelia Jimenez Gomez as private dono

Cytochrome c autocatalyzed carbonylation in the presence of hydrogen peroxide and cardiolipins

15 pages, 9 figures, 2 tablesCytochrome c (cyt c) is a small hemoprotein involved in electron shuttling in the mitochondrial respiratory chain and is now also recognized as an important mediator of apoptotic cell death. Its role in inducing programmed cell death is closely associated with the formation of a complex with the mitochondrion-specific phospholipid cardiolipin (CL), leading to a gain of peroxidase activity. However, the molecular mechanisms behind this gain and eventual cyt c autoinactivation via its release from mitochondrial membranes remain largely unknown. Here, we examined the kinetics of the H2O2-mediated peroxidase activity of cyt c both in the presence and absence of tetraoleoyl cardiolipin (TOCL)- and tetralinoleoyl cardiolipin (TLCL)-containing liposomes to evaluate the role of cyt c–CL complex formation in the induction and stimulation of cyt c peroxidase activity. Moreover, we examined peroxide-mediated cyt c heme degradation to gain insights into the mechanisms by which cyt c self-limits its peroxidase activity. Bottom-up proteomics revealed >50 oxidative modifications on cyt c upon peroxide reduction. Of note, one of these by-products was the Tyr-based “cofactor” trihydroxyphenylalanine quinone (TPQ) capable of inducing deamination of Lys ϵ-amino groups and formation of the carbonylated product aminoadipic semialdehyde. In view of these results, we propose that autoinduced carbonylation, and thus removal of a positive charge in Lys, abrogates binding of cyt c to negatively charged CL. The proposed mechanism may be responsible for release of cyt c from mitochondrial membranes and ensuing inactivation of its peroxidase activityThis work was supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept for the SysMedOS project, Deutsche Forschungsgemeinschaft (DFG) Grant FE-1236/3-1 (to M. F.), European Regional Development Fund (ERDF; European Union and Free State Saxony) Grants 100146238 and 100121468 (to M. F.), and a Xunta de Galicia postdoctoral scholarship (to L. M.)Peer reviewe

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

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

Serotonin as a putative scavenger of hypohalous acid in the brain

Neurodegenerative disorders represent the culmination of numerous insults including oxidative stress. The long etiology of most of these disorders suggests that lessening the effects of one of more of the insults could significantly delay disease onset. Antioxidants have been tested as possible therapeutics for neurodegenerative disorders, but with little success. Here we report that serotonin acts as a scavenger of hypochlorous acid (HOCl) in the brain. Serotonin was shown to prevent the oxidation of 2-thio-5-nitrobenzoate by HOCl in a biphasic manner. The first phase was a partial scavenging that occurred at concentrations of serotonin that exceeded those of HOCl. (1)H-NMR studies indicated that HOCl chlorinates both the aryl and akyl nitrogen atoms of serotonin. Thus, the residual but lower oxidation of 2-thio-5-nitrobenzoate that occured during the first phase of scavenging is likely to due to formation of serotonergic chloramines. A second phase of scavenging occurred at concentrations of HOCl that exceeded those of serotonin. Under these conditions, the chlorinated serotonin polymerized and formed inert aggregates. Serotonin was further shown to prevent the loss of cells and cellular α-ketoglutarate dehydrogenase activity caused by HOCl. Extracellular concentrations of serotonin in the brain can be elevated with selective serotonin reuptake inhibitors and suggests that such compounds could be used to increase the cerebral antioxidant capacity. Acute administration of selective serotonin reuptake inhibitors to mice treated with endotoxin partially mitigated sickness behavior and protein chlorination in the brain. These observations suggest that serotonin may act to suppress chlorinative stress in the brain