Parkinson’s disease (PD) is an age-related, progressive neurodegenerative disease. After Alzheimer’s disease, PD is the second most common neurodegenerative disease affecting almost 1% of the population over the age of 65 and 5% of the population over the age of 85. Parkinson’s disease is characterized by the loss of dopaminergic neurons in the substantia nigra region of the brain. Given the role of dopaminergic neurons in regulating motor activity, parkinson’s disease is also known as a ‘movement disorder’. Due to the increasing lifespan of the population, the number of people suffering from parkinson’s disease is likely to double by 2040. The research described herein will provide insight into possible therapies for PD. In particular, we will explore the potential of botanical extracts enriched in different phytochemicals as candidates for PD therapy or as agents to reduce PD risk.
The main symptoms experienced by PD patients arise from motor dysfunction and include resting tremor, rigidity and difficulty initiating and sustaining movements. The non-motor symptoms of PD generally occur at the later stage of the disease and include depression, hallucinations, sleep disorder and memory loss. Pathologically, the brains of PD patients show a substantial loss of dopaminergic neurons in the substantia nigra region of the brain. It is believed that by the time the symptoms appear about 50% of the dopaminergic neurons are lost or 80% of striatal dopamine is lost. A recent study showed that a 14-23 % loss of nigral neurons and a 14-37 % loss of striatal dopamine was sufficient to induce mild parkinsonism in nonhuman primates. Another pathological hallmark of PD is the presence in surviving neurons of Lewy bodies and Lewy neurites, which are protein inclusions found in the cytoplasm and neurites respectively. It is an established fact that these protein inclusions contain aggregated forms of the protein alpha synuclein (αSyn), and as a result PD is referred to as a synucleinopathy.
Mitochondrial Dysfunction in Parkinson’s Disease
A role for mitochondrial dysfunction in PD pathogenesis is suggested by the fact that toxins linked to the disease, including MPTP and rotenone, are potent inhibitors of mitochondrial complex I. Moreover, a number of PD-related proteins have been shown to be involved in mitochondrial function. As discussed above, under conditions of oxidative stress, DJ-1 translocates to mitochondria to carry out its protective activity, and DJ-1 deficiency results in mitochondrial impairment. Parkin, a protein encoded by the PARK2 gene, and PINK1 (PTEN induced putative kinase), encoded by the PARK6 gene, are both associated with autosomal recessive juvenile- or early-onset Parkinsonism. Parkin and PINK1 both interact with different regions of mitochondria and protect cells by inhibiting the mitochondrial (intrinsic) apoptosis pathway. Parkin and PINK1 deficiency has been shown to cause mitochondrial impairment along with an imbalance in mitochondrial fission and fusion. Additional evidence suggests that αSyn plays a role in modulating mitochondrial linked complex I and III activity through effects on mitochondrial lipid composition. In contrast, αSyn is also thought to undergo a toxic gain of function that results in mitochondrial impairment. One group reported that αSyn contains a cryptic mitochondrial targeting sequence that enables the protein to associate with the inner mitochondrial membrane, resulting in impairment of complex I activity. Both wild type and mutant forms of αSyn have been shown to induce mitochondrial dysfunction. αSyn has been shown to localize to the mitochondria and affect the process of mitochondrial fission and fusion, required to maintain mitochondrial homeostasis. In summary, multiple lines of evidence from neuropathological, toxicological, and genetic studies suggest that mitochondrial dysfunction plays an important role in PD pathogenesis.
Glial Activation in Parkinson’s Disease
The activation of glial cells (microglia and astrocytes) plays an important role in the pathogenesis of PD. Under normal conditions, microglia and astrocytes not only provide nutrients to neurons but also fulfill an immune surveillance role. In response to various inflammatory stimuli, glial cells become activated and release proinflammatory molecules such as cytokines and interleukins. Activated glial cells also release ROS and reactive nitrogen species (RNS) due to the activation of enzymes such as NADPH oxidase and nitric oxide synthase. Although the activation of glial cells is a part of the brain immune response, in cases of PD and other neurodegenerative diseases excessive glial cell activation can be deleterious to neurons. Consistent with this idea, postmortem analysis of PD brains show evidence of microglial activation and increased levels of pro-inflammatory molecules. PD-related toxins such as rotenone, paraquat, and 6-OHDA (204) as well as exogenous aggregated αSyn have been shown to cause glial activation. ROS and αSyn oligomers produced and released by dopaminergic neurons are thought to trigger microglial/astrocytic activation, resulting in the release of pro-inflammatory molecules and ROS from these cells and leading to a vicious cycle of neurotoxicity and glial activation. Dopaminergic neurons may be more vulnerable to glial activation given the abundance of microglial cells in the substantia nigra. Interestingly, lipopolysaccharide (LPS), a classic inflammatory agent that triggers astrocyte and microglial activation, has been shown to induce dopaminergic cell death, providing further evidence of a role for glial activation in the loss of dopaminergic neurons.
UPS and Autophagy in Parkinson’s Disease
The ubiquitin proteasome system (UPS) is responsible for the degradation of normal as well as misfolded/damaged cellular proteins. Proteins to be degraded are first polyubiquitinated on lysine residues and then subsequently degraded by the 26S proteasome, a multisubunit proteolytic complex. Postmortem analysis of nigral tissue from PD patients shows a reduction in proteasomal activity. It is hypothesized that protein aggregates in PD can inhibit the UPS, and in turn the loss of UPS function can induce oxidative stress. Overex
Besides the UPS, autophagy (or the autophagy-lysosomal pathway) is a major pathway involved in the degradation of damaged cellular proteins and organelles. There are three types of autophagy in mammals: (i) microautophagy, involving direct engulfment of cytoplasmic components to be degraded by lysosomes; (ii) CMA, involving the targeting of cytoplasmic components to lysosomes through the participation of molecular chaperones; and (iii) macroautophagy (referred herein as autophagy), involving sequestration of organelles and cytoplasmic components by double membrane-bound structures called ‘autophagosomes’, the contents of which are degraded by lysosomal proteases following autophagosome-lysosome fusion. Although UPS and autophagy are two separate degradation pathways, evidence suggests that a cross talk exists between the two pathways, wherein inhibition of the UPS activates autophagy and autophagy deficiency impairs flux of the UPS.
Dysregulation of autophagy has been linked to PD pathogenesis. Studies have shown that αSyn is a substrate for not only the UPS but also autophagy and CMA. Interestingly, mutated αSyn has been shown to interfere with autophagy, whereas mutant and dopamine-modified forms of αSyn have been shown to inhibit CMA, thus increasing protein aggregation. ATP132, a lysosomal ATPase encoded by the gene PARK 9 is associated with autosomal recessive PD, and ATP13A2 mutations have been shown to result in dysregulation of autophagy and aggregation of αSyn. LRRK2, a leucine-rich repeat kinase 2 encoded by the gene PARK8 is associated with autosomal dominant PD. Studies suggest that LRKK2 is involved in regulation of autophagy and that the G2019S mutation (the most prevalent mutation of LRRK2) has been associated with modulation of autophagy. Additionally, evidence suggests that PD-related insults rotenone, PQ and MPTP result in dysregulation of the autophagy pathway.