Molecular aspects of dopaminergic neurodegeneration: gene-environment interaction in parkin dysfunction

Abstract

Parkinson's disease (PD) is a common neurodegenerative movement disorder that is characterized pathologically by a progressive loss of midbrain dopaminergic neurons and by protein inclusions, designated Lewy bodies and Lewy neurites. PD is one of the most common neurodegenerative diseases, affecting almost 1% of the population over 60 years old. Although the symptoms and neuropathology of PD have been well characterized, the underlying mechanisms and causes of the disease are still not clear. Genetic mutations can provide important clues to disease mechanism, but most PD cases are sporadic rather than familial; environmental factors have long been suspected to contribute to the disease. Although more than 90% of PD cases occur sporadically and are thought to be due, in part, to oxidative stress and mitochondrial dysfunction, the study of genetic mutations has provided great insight into the molecular mechanisms of PD. Furthermore, rotenone, a widely used pesticide, and paraquat and maneb cause a syndrome in rats and mice that mimics, both behaviorally and neurologically, the symptoms of PD. In the current review, we will discuss various aspects of gene-environment interaction that lead to progressive dopaminergic neurodegenration, mainly focusing on our current finding based on stress-mediated parkin dysfunction.

Keywords: Parkinson’s disease; dopaminergic; environment; gene; parkin.

Figure 1

An interplay between gene and environment affecting various stages of progressive mechanisms leading to the neuronal death in PD. The central generation of free radicals after exposure to environmental toxins or decreased UPS function and protein aggregate formation due to genetic defect is thought to be a major mechanism of dopaminergic cell death in PD.

Figure 2

Gene-environment interplay induces complex crosstalk leading to the increased level of oxidative stress in dopaminergic neurons. Various pathways and their dysfunctions resulting from genetic defects in PD-related genes such as α-synuclein, Parkin, DJ-1, LRRK2, PINK 1 lead to molecular mechanisms that result in an increased oxidative stress. Similarly, stress and trauma that might be physical or induced by environmental toxicants can inhibit proper functions of the gene products of PD-related genes such as Parkin, DJ-1 or PINK 1 or induce mitochondrial Complex I inhibition or neuroinflammation resulting in increased oxidative stress thus leading to neuronal cell death [9].

Figure 3

Environmental toxin stress results in tyrosine phosphorylation of parkin in SH-SY5Y cells expressing myc-parkin. Cells were treated with 250 μM paraquat or 2.5 μM rotenone for 24 hr. In some cases, cells were pretreated with 10 μM STI-571 6 hours prior to toxin treatment. RIPA lysates were prepared and subjected to immunoprecipitation with anti-parkin antibody and immunoblotted with antibodies as shown in the figure.