Parkinson’s disease is a disease of the brain affecting the body’s motor system.2 While the exact cause of the disease is still unknown, there is evidence showing that a patient’s genetics and environmental circumstances play an important role.4,10 Patients suffering from Parkinson’s disease exhibit abnormalities in a portion of their midbrain called the substantia nigra, which is important to our body’s reward system and movement.2,6 These patients have abnormal clusters of neurons in the central nervous system that form dopamine.8
In addition to physical anomalies in the substantia nigra, patients with this disease have mutations in their cellular functions including transportation between vesicles, homeostasis of mitochondria generation and degradation, lysosomal functions, and stabilization of microtubules.3 The mutations are located on genes that code for important proteins involved in cellular functions like α-synuclein (SNCA), PARKIN, PINK1, LRRK2 and DJ-1.
α-synuclein is a key protein that is encoded within the SNCA gene.1 It is major contributor of Parkinson’s disease and likes to form oligomers in neuronal cells. First, this protein disrupts mitochondrial function by inhibiting ATP use.3 The n-terminus of the α-synuclein binds to the negatively charged phospholipids on the mitochondrial membrane.3,9 Within lysosomal degradation, α-synuclein can cause inflammation because the migroglial cells in the brain have an inflammatory response function that reacts to the α-synuclein oligomers.1,9
The immune system reacts to these α-synuclein oligomers to produce the neuro-inflammatory signals, and the membrane damage oligomers try to fix the damage by allowing calcium to flow into the plasma membrane.1,9 The excessive calcium intake leads to cellular distress and it blocks the lysosome and the autophagic pathway.1 As a result, α-synuclein oligomers accumulate within the cell, leading to multiple detrimental effects. Synaptic dysfunction oligomers impair the interaction of multiple important proteins including a dopaminergic catabolism which promotes oligomerization of α-synuclein. Ultimately, this leak at the synapse leads to the loss of dopamine.8
The loss of dopamine leads to neurodegeneration, in patients with Parkinson’s disease.8 In patients without Parkinson’s disease, there are many dopaminergic neurons in the mitochondria because they require a lot of ATP. Due to this high density in mitochondria, dopaminergic neurons respond more greatly to mitochondrial dysfunction.3 In neurotypicals, α-synuclein has a α-helical shape to bind to the lipid membrane.1,9 In patients with Parkinson’s disease, α-synuclein oligomers disrupt this natural binding.1,9 As a result, α-synuclein increases oxidative stress because dopamine becomes oxidized and turns into reactive oxygen species and other reactive intermediates.8
Another mechanism by which α-synuclein increases oxidative stress is by chemical interactions of detergents.1,9 α-synuclein oligomers can be resistant to solubilizing in SDS if dopamine can resist oxidative stress from with α-synuclein. Dopamine oligomers can form cross links with α-synuclein through covalent linking, hydrogen bonding, and other hydrophobic interactions between the molecules.8
Additional proteins like PINK1 and PARKIN are also important contributors to Parkinson’s disease. They are responsible for the selective degradation of degenerative mitochondria by mitophagy.5,7 In the dysfunctional mitochondria of patients with Parkinson’s disease, PINK1 cannot transport into the inner mitochondrial membrane.5 PARKIN is able to partially localize into the outer mitochondrial membrane.5 At this instance, DJ-1, another important protein for Parkinson’s disease re-enteres the mitochondria due to the increase in oxidative stress. PINK1 identifies the damaged mitochondria and destroys them.5,7 The accumulation of the PINK1 protein on the mitochondrial outer membrane leads to the activation of the E3 (ubiquitin ligase) activity on PARKIN; thereby, attracting PARKIN to the damaged mitochondria.7 PARKIN ubiquitinates proteins on the mitochondria to bind autophagy proteins like p62/SQSTM1 or LC3 to the mitochondria for mitophagy.7 PINK1 and PARKIN quarantines the damaged mitochondria.3 If either of these proteins are overexpressed, it can result in mitochondrial arrest.5,7
VMAT2 is an integral membrane protein involved in transporting neurotransmitters from the cytol to the vesicles.11 It is expressed in monoaminergic neurons in the sympathetic nervous system of the central nervous system, mast cells of the immune system, and histamines in the digestive system. VMAT2 allows neurotransmitters to be released into the synaptic cleft; therefore, if there is a mutation in the VMAT2 protein, it can prevent dopamine release.8 In patients with Parkinson’s Disease, VMAT2 does not work like it should. Each time that VMAT2 transports a monoamine molecular to the lumen, two protons leave the lumen. As a result, VMAT2 is an important protein to mediating dopamine transport in the axons terminals of neurons.
Research shows that a defect in vesicle trafficking is evident in patients with Parkinson’s disease.2 Rab For instance, GTPase is the enzyme substrate for LRRK2 and an increase in LRRK2 leads to an increase in the phosphorylation of α-synuclein and other α-synuclein oligomers.2,10 When LRRK2 levels were lowered, there was an increase in small α-synuclein inclusions.10
In summary, there are five critical proteins in Parkison’s disease called α-synuclein (SNCA), PARKIN, PINK1, LRRK2 and DJ-1. The central protein is α-synuclein, and it increases oxidative damage due to mitochondrial dysfunction. PINK1 and Parkin are related to lysosomal degradation. As a result, patients with a genetic defect of either one of these proteins experience increased oxidative stress from the production of reactive oxygen species. Parkin on the other hand, is a key protein for vesicle and organelle trafficking. The VMAT2 dopamine transporter is in the central nervous system, immune system, and digestive system. Increasing VMAT2 transporter expression allows for protection of dopaminergic neurons from cellular damage caused by dopamine recycling and synthesis. Lastly, the cooperative relationship between LRRK2 protein and Rab trafficking proteins are important for maintaining α-synuclein and reducing misfolded α-synuclein and α-synuclein oligomers. LRRK2 and Rab proteins cooperate together to control the damaging effects of α-synuclein.
References:
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