Parkinson’s disease is a prominent progressive neurological disorder that involves the loss of dopaminergic neurons in the substantia nigra pars compacta (SN). This degeneration is associated with motor disturbances including tremor, rigidity, and bradikinesia (slowness of movement).
Various factors, including heavy metals and pesticides, have been implicated.
Although the cause of sporadic PD is not fully understood, various factors, including heavy metals and pesticides, have been implicated. Epidemiological studies also show that the risk of PD in humans is strongly increased by combined exposure to the fungicide Maneb (manganese ethylene-1,2-bisdithiocarbamate) and the herbicide paraquat (1,1-dimethyl-4,4-bipyridinium).
These two pesticides are commonly used concurrently in agriculture. Owing to this fact and to shed light on the neurobiology of Parkinson’s disease the Maneb and paraquat-induced model of PD had been developed previously.
The pathological features of PD include an abnormal accumulation of the protein α-synuclein in the surviving dopaminergic neurons in the nigrostriatal pathway.
In pesticide-related PD, mitochondrial dysfunction and α-synuclein oligomers have been strongly implicated, but the link between the two has not yet been understood. Similarly, the biological effects of α-synuclein or its radical chemistry in PD is largely unknown. Mitochondrial dysfunction during PD pathogenesis leads to release of cytochrome c in the cytosol. Once in the cytosol, cytochrome c has one of two fates: It either binds to apaf1 and initiates apoptosis or can act as a peroxidase. We hypothesized that as a peroxidase, cytochrome c leaked from mitochondria can form radicals on α-synuclein and initiate its oligomerization.
We provide extensive evidence that α-synuclein affects several biological pathways, which ultimately contribute to neuronal death.
Therefore, we aimed to investigate (I) a possible correlation between mitochondrial dysfunction concurrent with cytochrome c release and the role of cytochrome c in α-synuclein radical formation, (II) the role of cytochrome c in α-synuclein oligomerization, and (III) the biological implications of α-synuclein radical formation or the role of α-synuclein per se in terms of its effects on biological pathways and neuronal death.
In this paper we report for the first time that cytochrome c plays crucial roles in α-synuclein radical formation and oligomerization. Also, we provide extensive evidence that α-synuclein affects several biological pathways, which ultimately contribute to neuronal death in the MP-induced mouse model of PD. Interestingly, the presence or absence of α-synuclein (in wild-type or α-synuclein knockout mice, respectively) determined all the difference in response to Maneb and paraquat co-exposure. Based on this study which shows centrality of α-synuclein, we suggest that experimental approaches which rely on scavenging α-synuclein radical or decreasing α-synuclein levels, can possibly lead to development of potential therapeutics for Parkinson’s disease.
- Centrality of α-synuclein in pesticide related Parkinson’s disease - 25th November 2016