Link Between Environmental Factors and Parkinson's Disease
Parkinson's Disease (PD) is the second most commonly diagnosed neurodegenerative disease behind Alzheimer's Disease (AD). PD occurs when dopamine producing neurons that control movement functions become impaired or die. After the neurons become impaired, dopamine levels drop, causing PD symptoms. The main symptoms are tremors, stiffness of limbs and trunk, slowness of movement, and impaired balance. However, people may experience a vast number of other symptoms.
Further, the brain cells of people diagnosed with PD contain Lewy bodies, which are clusters of the pre-synpatic neuronal protein alpha-synuclein. Alpha-synuclein misfolding and aggregation is the main event in the development of PD.
PD can be sporadic or familial, however, there is evidence that suggests exposure to specific environmental factors may play a role in PD pathogenesis. The most prominent risk factor for PD is age, affecting people around the age of 60. However, 5 to 10 percent of people develop early-onset PD, which may appear before the age of 50.
Recently, there has been an increase in research relating to environmental factors that contribute to PD. First, overexposure to specific heavy metals, such as manganese, has been suspected to aggravate or cause neurodegeneration. High-level exposure of manganese from certain occupations, like welding and mining, causes dopaminergic cell death. "PD and Mn-induced parkinsonism share some similar cellular mechanisms including energy deficits, altered mitochondria function, protein aggregation, UPS dysfunction, and neurotoxic effects on dopamine neurons."* UPS is the Ubiquitin Proteasome System that is an important and highly regulated mechanism in protein degradation.
Second, rotenone, a naturally occurring pesticide used in organic farming, is a suspected environmental factor that leads to PD related pathogenesis. Rotenone accumulates in the mitochondria and has toxic effects by inhibiting mitochondrial complex I, leading to insufficient ATP synthesis. Additionally, rotenone is toxic to nigrostriatal dopamine neurons and causes Lewy-body-like inclusions that contain alpha-synuclein.
Third, long-term exposure to ambient air pollution is thought to contribute to PD. Toxins in ambient air pollution have been implicated to promote brain inflammation and oxidative stress that has a supposed contribution to the progression of PD. For instance, nitrogen dioxide has an adverse effect on mitochondria. Nitrogen dioxide exposure induces mitochondrial morphological changes that result in reduced ATP production.
The identification of ubiquitin in Lewy bodies offers compelling evidence for the involvement of altered ubiquitin signaling and disrupted protein quality control in PD. There is evidence that mitochondrial dysfunction is associated with PD. PINK 1, a kinase. and Parkin, a ubiquitin ligase, are important in clearing damaged mitochondria (mitophagy). It is a chain reaction that begins when PINK1 kinase activates ubiquitin ligase Parkin. Subsequently, Parkin ubiquitylates the damaged mitochondria through lysine 6-linked (K6) poly-ubiquitin chain to promote its clearance.
LifeSensors has developed highly selective poly-ubiquitin binding affinity matrices called TUBEs (Tandem Ubiquitin Binding Entities). LifeSensors has discovered poly-ubiquitin signatures as novel early stage biomarkers for PD. We are currently developing K6 TUBEs, which will be an essential tool to understand the effects of the different environmental agents in characterizing the mechanism of action.
For more information on how TUBEs function and ubiquitin research, please visit our webpage.