Pathophysiology of Parkinson's disease

The first major proposed cause of neuronal death in Parkinson's disease involves the bundling (oligomerization) and mis-folding of proteins. The protein alpha-synuclein, which is encoded by the SNCA gene, has increased presence in the brains of Parkinson's Disease patients where it aggregates to form Lewy bodies (shown to left) in neurons. Lewy bodies are recognized as a pathological marker of Parkinson's disease. Alpha-synuclein appears to be a key link between reduced DNA repair and Parkinson's disease. Alpha-synuclein activates ATM (ataxia-telangiectasia mutated), a major DNA damage repair signaling kinase. Alpha-synuclein binds to breaks in double-stranded DNA and facilitates the DNA repair process of non-homologous end joining. Reduced expression of α-Syn may lead to increased formation of DNA double-strand breaks (DSBs) and reduced ability to repair DSBs. Cytoplasmic aggregation of alpha-synuclein to form Lewy bodies may reduce alpha-synuclein availability in the nucleus leading to decreased DNA repair, increased DNA double-strand breaks and increased programmed cell death of neurons. Body-first and brain-first models potentially explain the connection of PD mechanisms with known environmental risk factors such as exposure to pesticides, industrial chemicals, and air pollution. Most toxicants are inhaled, ingested, or both. In the nasal cavity and gut, they engage directly with mucosal surfaces where inflammation can occur. Pathways from the olfactory system and gut to the brain are well established. ==Autophagy disruption==

The second major proposed mechanism for neuronal death in Parkinson's disease, autophagy, is a mechanism by which inner components of the cell are broken down and recycled for use. Autophagy has been shown to play a role in brain health, helping to regulate cellular function. Disruption of the autophagy mechanism can lead to several different types of diseases including Parkinson's disease. Autophagy dysfunction in Parkinson's disease also has been linked to dysregulated mitochondria degradation (mitophagy). ==Mitochondrial dysfunction==

The third major proposed cause of cell death in Parkinson's disease involves the energy-generating mitochondrion organelle. In Parkinson's disease, mitochondrial function is disrupted, inhibiting energy production and resulting in death. One mechanism behind mitochondrial dysfunction in Parkinson's disease involves the PINK1 and Parkin pathway, which tags damaged mitochondria for removal (mitophagy). PINK1 accumulates on the outer surface of impaired mitochondria. Ubiquitin is phosphorylated by PINK1 to activate Parkin, which tags mitochondrial proteins for degradation. In Parkinson's disease, mutations of the genes coding PINK1 and Parkin impair normal mitochondrial function, leading to defective clearance of damaged mitochondria. Another mitochondrial-related mechanism for cell death in Parkinson's disease is the increased generation of Reactive oxygen species (ROS). Mitochondrial dysfunction in PD patients reduces adenosine triphosphate (ATP) synthesis and increases generation of ROS, damaging mitochondrial membranes and releasing factors involved in apoptosis. Mitochondrial dysfunction disrupts cellular energy production and increases oxidative stress. Oxidative stress causes oxidative DNA damage. Oxidative stress appears to have a role in mediating multiple separate pathological events in pathways that ultimately result in cell death in PD. Alpha-synuclein and dopamine levels are involved in amplifying oxidative stress. Mitochondrial dysfunction also triggers inflammation by activating damage-associated molecular patterns (DAMPs), inflammatory cells, and intracellular protein complexes inside inflammatory cells called inflammasomes. ==Neuroinflammation==

Neuroinflammation is considered a contributing mechanism in Parkinson's disease as well as other neurodegenerative diseases. One major cell type involved in neuroinflammation is the microglia. Microglia are recognized as the innate immune cells of the central nervous system. Research has shown lasting activation of the brain's immune cells, microglia, in regions affected by the disease, suggesting that inflammation may play a role in the gradual loss of dopamine-producing neurons. While immune responses can be protective in the short term, chronic inflammation may damage neurons over time. Dopaminergic neurons appear to be particularly vulnerable under inflammatory conditions. The normal production and breakdown of dopamine already place these cells under higher stress than other neurons. When inflammation is present, this may increase the neurons' susceptibility to damage and speed up degeneration. Changes in dopamine signaling may then influence immune activity in the brain, creating a feedback loop to further worsen neuronal loss. Microglia generate reactive oxygen species (ROS) and release signals to recruit peripheral immune cells for an inflammatory response. ==BBB breakdown==

The fifth proposed major mechanism for cell death is the breakdown of the blood–brain barrier (BBB). The BBB has three cell types which tightly regulate the flow of molecules in and out of the brain: endothelial cells, pericytes, and astrocytes. Neuroinflammation causes the blood-brain barrier (BBB) to become more permeable, allowing dangerous substances and inflammatory cells to enter the brain and interfere with metabolic functions. Interaction between the VEGF protein and its receptors regulates the proliferation, migration, and survival of endothelial cells. Disruption can interfere with cell growth and prevent new capillary formation via angiogenesis. ==Impact on locomotion==

Coordinated movement is a complex spatiotemporal activity. Dopamine is a neurotransmitter which modulates the activity of motor neurons in the central nervous system, in particular in the substantia nigra (SN). The regulation of dopamine release is critical for locomotor activity. Dopamine is involved in the activity of both direct and indirect pathways in the circuits of the basal ganglia, activating the direct pathway (via D1 receptors) while inhibiting the indirect pathway (via D2 receptors). The two pathways work synergistically to initiate and control movement. This interferes with motor planning, execution, and adaptability, causing impairments in gait parameters such as walking speed, stride length, cadence, and variability. ==See also==