Caenorhabditis elegans Model Studies Show MPP⁺ Is a Simple Member of a Large Group of Related Potent Dopaminergic Toxins

Abstract

Although the causes of Parkinson’s disease (PD) are not fully understood, the consensus is that a combination of genetic and environmental factors plays a major role. The discovery that the synthetic chemical, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-derived N-methyl-4-phenylpyridinium (MPP+), recapitulates major pathophysiological characteristics of PD in humans and other mammals has provided the strongest support for this possibility; however, several key aspects of the mechanism remain unclear. In contrast to the widely accepted view that MPP+ is structurally unique and optimal for selective dopaminergic toxicity, previous in vitro studies have suggested that MPP+ is most likely a simple member of a large group of related dopaminergic toxins. Here we provide first in vivo evidence to support the above possibility using Caenorhabditis elegans PD models. We also provide in vivo evidence to show that the inherent predisposition of dopaminergic neurons to produce high oxidative stress and related downstream effects when exposed to MPP+ and related mitochondrial toxins is responsible for their selective vulnerability to these toxins. More significantly, present findings suggest that if this broad group of MPP+ related dopaminergic toxins are present in work places or in the environment, they could cause far-reaching public health consequences.

Longitudinal in vivo metabolic labeling reveals tissue-specific mitochondrial proteome turnover rates and proteins selectively altered by parkin deficiency

“…In the hepatic mitochondrial proteome, alterations in the abundance of proteins related to pathways of neurodegeneration were observed. A majority among these were multiple subunit components of respiratory Complex I, which is theorized to be to particularly susceptible to proteopathic damage 92 , 94 , 95 and is the target of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, a neurotoxin which results in a PD-like syndrome in people 96 , and used to model PD in rodents, and its analogues 43 , 97 – 99 .…”

Advances of H2S in Regulating Neurodegenerative Diseases by Preserving Mitochondria Function

“…Aluminium is a toxic metal ubiquitously present on earth that impairs mitochondrial bioenergetics and leads to cognitive disorder once it enters the brain [ 36 ]. Moreover, it has been found that N-methyl-4-phenylpyridinium (MPP + ) related compounds are dopaminergic toxins that can induce mitochondrial oxidative stress and dysfunction [ 37 ]. Thus, they are usually used to induce animal models of PD.…”