br Parkinson s Disease and the immune
Parkinson’s Disease and the immune system Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, after Alzheimer’s, which affects 10 million people globally and is characterized by rigidity, bradykinesia, tremors, and gait instability (O’sullivan et al., 2007). The pathological hallmarks of PD include reduced dopamine due to loss of dopaminergic neurons in the basal ganglia and the substantia nigra (SN) (Hirsch et al., 1988, Fearnley and Lees, 1991), as well as accumulation of α-synuclein, ubiquitin, and neurofilaments, also called Lewy bodies (LB). Pharmacological dopaminergic substitution therapy remains a central treatment for symptom management. Immune-related side effects have been reported in patients taking antiparkinson’s medications such as L-DOPA, dopamine agonists, and catabolic inhibitors (Table 2) suggesting alterations in peripheral dopamine levels may lead to dysfunctional immune responses. Indeed, plasma dopamine is elevated in patients on dopamine substitution therapy compared to healthy controls (Kustrimovic et al., 2016) and thus this may lead to increased dopamine signaling on immune cells. On a more clinically relevant scale, L-DOPA treatment in a 6-hydroxydopamine rat model of Parkinson’s increases immunogenic response after xenogeneic ventral mesencephalon graft (Breger et al., 2017), implicating over-activation of microglia. Additionally, PD patients on dopaminergic therapies showed increased Ellipticine of D1R on CD4+ T-cell when compared to drug-naïve patients (Kustrimovic et al., 2016). This evidence, along with the report by Cordano and colleagues, shows that while dopaminergic therapies are aimed at rescuing CNS dopamine levels, they also have effects on peripheral dopamine tone and, consequently, immunological effects. This then further implies that the dysregulation of dopamine in Parkinson’s Disease may alter peripheral immunity, suggesting a connection between central dopamine, peripheral dopamine, and immune function. Braak and colleagues developed a widely-accepted hypothesis suggesting PD starts in the gastrointestinal tract, spreading to the dorsal motor nucleus of the vagus nerve, and then throughout the CNS (Braak et al., 2003a, Braak et al., 2003b). Although the exact etiology is still unknown, environmental, genetic, and immune system interactions are reported as the most common contributing factors in the disease onset and progression (Olson and Gendelman, 2016). Therefore, we review the literature concerning the for the role of the immune system in PD, including involvement of neuroinflammation and peripheral immunity. Consistent with the Braak hypothesis of a peripheral origin for PD, we specifically explore the possibility of dopamine-related peripheral immune cell dysfunction association to PD pathogenesis and/or progression.
Conflict of interest statement
Ionotropic glutamate receptors mediate excitatory synaptic transmission throughout the central nervous system (CNS). These fast-acting, glutamate-gated ion channels are largely postsynaptic and come in two classes: NMDA receptors and AMPA/kainate receptors. The roles of ionotropic glutamate receptors in plasticity and rapid memory acquisition are well known. For many years it was believed that glutamate activated only ionotropic receptors, and glutamate-induced metabolic responses were linked to calcium entry through their associated channels; however, metabotropic glutamate receptors (mGlu) are G protein-coupled and activate signaling pathways indirectly, including ion channel-mediated pathways, synaptic plasticity, and neurotransmitter release . They are located on presynaptic and postsynaptic membranes of glutamatergic neurons, as well as on glial cells and non-glutamatergic neurons, where they influence neuropeptide and monoamine release. Metabotropic glutamate receptors are linked to transient receptor potential (TRP) channel activation in substantia nigra dopaminergic neurons, suggesting that they participate in striatal glutamate- and GABA-mediated synaptic transmission . Similarly to glutamate receptors, GABA receptors come in two classes: GABA receptors are ionotropic (Cl channels), and GABA receptors are metabotropic . Acetylcholine receptors show a similar duality, and nicotinic receptors are the ionotropic class and muscarinic receptors the metabotropic class. Glutamate, GABA, acetylcholine, and many other ligands activate both metabotropic and ionotropic receptors .