Parkinson's disease: Autoimmunity and neuroinflammation

Abstract

Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and warrant further investigation.

Regulation of Ketone Body Metabolism and the Role of PPARα

“…While FFAR3 is expressed in multiple tissues, in the brain, it enhances sympathetic nervous system activity, which results in increased metabolic rate that is blocked by increasing bHB concentrations [78]. These exciting new data reveal that ketone bodies have intrinsic signaling capacities that in some cases may impact cellular or organismal metabolism, and in others, affect processes such as inflammation, which are known to be involved in certain neurological conditions such as Alzheimer’s, Parkinson’s, and brain cancers [80,81,82]. This highlights the importance in further understanding the complex roles of ketone bodies in modulating cellular signaling responses.…”

A Case-Control Association Study of RANTES (-28C>G) Polymorphism as a Risk Factor for Parkinson’s Disease in Isparta, Turkey

“…Oxidative stress, mitochondrial dysfunction, excitotoxicity, accumulation of altered proteins, and apoptosis have been implicated as cellular and molecular mechanisms that might be responsible for neuronal degeneration in PD [3]. Results of postmortem and in vivo studies in patients and studies in animal models suggest that neuroinflammation might also contribute to neuronal degeneration [3–10]. The following symptoms in PD patients indicate that there are neuroinflammatory processes in the affected brain regions: the presence of activated microglial cells, reduced density of astrocytes in the substantia nigra, the presence of cytotoxic T-lymphocytes in the substantia nigra adjacent to blood vessels and dopaminergic neurons, and increased concentrations of tumor necrosis factor-alpha, beta2-microglobulin, transforming growth factor-alpha, transforming growth factor-1beta, interferon gamma, and interleukins-1beta, 6, and 2 in the striatum, serum, or cerebrospinal fluid [3].…”

Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

“…Neurodegeneration in PD may be accompanied by an inflammatory reaction, characterized by activation of microglia, which leads to production of a number of inflammatory mediators (e.g., NF- κ B, interleukin-1 (IL-1), IL-6, IL-1 β , cyclooxygenase-2 (COX-2), tumoral necrosis factor- α (TNF- α ), inducible nitric oxide synthase (iNOS), interferon- γ ) and increased expression of different proinflammatory cytokines by glial cells. Besides, an increase in the level of these components in the substantia nigra and in the cerebrospinal fluid (CSF) and an elevation of γ / δ + T cells in the peripheral blood and CSF of patients with PD were also reported [101, 106, 107]. This increase in the proinflammatory cytokine levels could switch on different apoptotic pathways involved in the degeneration of DAergic neurons [94].…”