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Pathophysiology

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Main article: Pathophysiology of Parkinson's disease
Parkinson's results from the death of dopamine-releasing neurons in the substantia nigra, seen by the loss of dark neuromelanin in the lower inset.

Main pathological feature is cell death of dopamine-releasing neurons within, among other regions, the basal ganglia, more precisely pars compacta of substantia nigra and partially striatum, thus impeding nigrostriatal pathway of the dopaminergic system which plays a central role in motor control.[1]

Neuroanatomy

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Three major pathways connect the basal ganglia to other brain areas: direct, indirect, and hyper-direct pathways, all part of the cortico-basal ganglia-thalamo-cortical loop.[2]

The direct pathway projects from the neocortex to putamen or caudate nucleus of the striatum, which sends inhibitory GABAergic signals to substantia nigra pars reticulata (SNpr) and internal globus pallidus (GPi).[2] This inhibition reduces GABAergic signaling to ventral lateral (VL) and ventral anterior (VA) nuclei of the thalamus, thereby promoting their projections to the motor cortex.[3]

The indirect pathway projects inhibition from the striatum to external globus pallidus (GPe), reducing its GABAergic inhibition of the subthalamic nucleus, pars reticulata, and internal globus pallidus. This reduction in inhibition allows the subthalamic nucleus to excite internal globus pallidus and pars reticulata, which in turn inhibit thalamic activity, thereby suppressing excitatory signals to the motor cortex.[2]

The hyperdirect pathway is an additional glutamatergic pathway that projects from the frontal lobe to the subthalamic nucleus, modulating basal ganglia activity with rapid excitatory input.[4]

The striatum and other basal ganglia structures contain D1 and D2 receptor neurons that modulate the previously described pathways. Consequently, dopaminergic dysfunction in these systems can disrupt their respective components—motor, oculomotor, associative, limbic, and orbitofrontal circuits (each named for its primary projection area)—leading to symptoms related to movement, attention, and learning in the disease.[5]

Mechanisms

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Neuronal cell death has been linked to numerous mechanisms, with the most prominent being the misfolding and aggregation of alpha-synuclein, oxidative stress, neuroinflammation, ferroptosis, mitochondrial dysfunction, and gut dysbiosis.[6]

Alpha-synuclein and Lewy bodies

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Alpha-synuclein, a protein involved in synaptic vesicle trafficking, intracellular transport, and neurotransmitter release, is considered one of the primary contributing factors for nigrostriatal neuron death in PD. When overexpressed or misfolded, it can form clumps[7] on axon terminals and other neuronal structures, particularly its typical locations: the cytoplasm, mitochondria and nucleus. These aggregates eventually lead to the formation of Lewy bodies. Their precursors, known as oligomers, along with initial deposits called pale bodies, are believed to play a direct role in neurodegeneration, while Lewy bodies are thought to serve as an indirect marker of disease progression.[8]

A vicious cycle linked to neurodegeneration involves oxidative stress, mitochondria, and neuroimmune function, particularly inflammation. Normal metabolism of dopamine tends to fail, leading to elevated levels of reactive oxygen species (ROS) which is cytotoxic and causes cellular damage to lipids, proteins, DNA, and especially mitochondria.[9] Mitochondrial damage triggers neuroinflammatory responses via damage-associated molecular patterns (DAMPs), resulting in aggregation of neuromelanin, and therefore, fueling further neuroinflammation by activating microglia.[10]

Ferroptosis is suggested as another significant mechanism in disease progression. It is characterized by cell death through high levels of lipid hydroperoxide.[11]

Other mechanisms include proteasomal and lysosomal systems dysfunction and reduced mitochondrial activity.[12] Iron accumulation in the substantia nigra is typically observed in conjunction with the protein inclusions. It may be related to oxidative stress, protein aggregation, and neuronal death, but the mechanisms are obscure.[13]

Neuroimmune interaction

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See also: Parkinson's disease and gut-brain axis

The neuroimmune interaction is heavily implicated in PD pathology. PD and autoimmune disorders share genetic variations and molecular pathways. Some autoimmune diseases may even increase one's risk of developing PD, up to 33% in one study.[14] Autoimmune diseases linked to protein expression profiles of monocytes and CD4+ T cells are linked to PD. Herpes virus infections can trigger autoimmune reactions to alpha-synuclein, perhaps through molecular mimicry of viral proteins.[15] Alpha-synuclein, and its aggregate form, Lewy bodies, can bind to microglia. Microglia can proliferate and be over-activated by alpha-synuclein binding to MHC receptors on inflammasomes, bringing about a release of proinflammatory cytokines like IL-1β, IFNγ, and TNFα.[16]

Activated microglia influence the activation of astrocytes, converting their neuroprotective phenotype to a neurotoxic one. Astrocytes in healthy brains serve to protect neuronal connections. In Parkinson's disease, astrocytes cannot protect the dopaminergic connections in the striatum. Microglia present antigens via MHC-I and MHC-II to T cells. CD4+ T cells, activated by this process, can cross the blood-brain barrier (BBB) and release more proinflammatory cytokines, like interferon-γ (IFNγ), TNFα, and IL-1β. Mast cell degranulation and subsequent proinflammatory cytokine release are implicated in BBB breakdown in PD. Another immune cell implicated in PD is the peripheral monocyte which has been found in the substantia nigra of people with PD. These monocytes can lead to more dopaminergic connection breakdown. In addition, monocytes isolated from people with Parkinson's disease express higher levels of the PD-associated protein, LRRK2, compared with non-PD individuals via vasodilation.[17] In addition, high levels of pro-inflammatory cytokines, such as IL-6, can lead to the production of C-reactive protein by the liver, another protein commonly found in people with PD, that can lead to an increase in peripheral inflammation.[18][19]

Peripheral inflammation can affect the gut-brain axis, an area of the body highly implicated in PD. People with PD have altered gut microbiota and colon problems years before motor issues arise.[18][19] Alpha-synuclein is produced in the gut and may migrate via the vagus nerve to the brainstem, and then to the substantia nigra.[undue weight? – discuss][better source needed][20]

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