Research Article: Necrosis, apoptosis, necroptosis, three modes of action of dopaminergic neuron neurotoxins

Date Published: April 25, 2019

Publisher: Public Library of Science

Author(s): Noëlle Callizot, Maud Combes, Alexandre Henriques, Philippe Poindron, Rodrigo Franco.

http://doi.org/10.1371/journal.pone.0215277

Abstract

Most of the Parkinson’s disease (PD) cases are sporadic, although several genes are directly related to PD. Several pathways are central in PD pathogenesis: protein aggregation linked to proteasomal impairments, mitochondrial dysfunctions and impairment in dopamine (DA) release. Here we studied the close crossing of mitochondrial dysfunction and aggregation of α-synuclein (α-syn) and in the extension in the dopaminergic neuronal death. Here, using rat primary cultures of mesencephalic neurons, we induced the mitochondrial impairments using “DA-toxins” (MPP+, 6OHDA, rotenone). We showed that the DA-Toxins induced dopaminergic cell death through different pathways: caspase-dependent cell death for 6OHDA; MPP+ stimulated caspase-independent cell death, and rotenone activated both pathways. In addition, a decrease in energy production and/or a development of oxidative stress were observed and were linked to α-syn aggregation with generation of Lewy body-like inclusions (found inside and outside the dopaminergic neurons). We demonstrated that any of induced mitochondrial disturbances and processes of death led to α-syn protein aggregation and finally to cell death. Our study depicts the cell death mechanisms taking place in in vitro models of Parkinson’s disease and how mitochondrial dysfunctions is at the cross road of the pathologies of this disease.

Partial Text

Parkinson’s disease (PD) is a common neurodegenerative movement disorder that affects around 1% of the population over the age of 70[1]. It is the second most common neurodegenerative disease after Alzheimer’s disease. The patients suffering from PD display symptoms of motor instabilities with resting tremor as the first symptom in 70% of the cases. Other clinical symptoms are rigidity, bradykinesia and postural instability, and often include cognitive impairment, depression and sleep disorders[2].

For the first time, to the best of our knowledge, the mode of cell death induced by DA-toxins (usually used as an inducer of PD in animals) on primary culture of mesencephalic dopaminergic neurons was dissected and compared. As already shown in literature, we observed that all these toxins were able (at different levels of intensity) to induce aggregation of α-syn in dopaminergic neurons [21–23]. Under our conditions, we also observed that many α-syn aggregates were found outside the neurons in the culture. These aggregates looked like LB, known to mainly consist of aggregated α-syn.

 

Source:

http://doi.org/10.1371/journal.pone.0215277

 

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