α-Synuclein and Noradrenergic Modulation of Immune Cells in Parkinson’s Disease Pathogenesis

Butkovich, Laura M.; Houser, Madelyn C.; Tansey, Malú G.

doi:10.3389/fnins.2018.00626

Cited by 29 publications

(24 citation statements)

References 201 publications

(241 reference statements)

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“…Pathologically, as shown in PD and other neurodegenerative diseases, multiple molecular pathways induced by BBB disruption, allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate neurodegeneration ( 10 ). Conversely, pathological products, such as α-synuclein, could easily enter into the blood from brain ( 11 ) and activate peripheral immune ( 12 ), which might further aggravate deterioration of systemic conditions. In addition, dysautonomia in MSA could have contributed to immune dysregulation, given the effect of sympathetic and parasympathetic innervation of major lymphoid organs.…”

Section: Introductionmentioning

confidence: 99%

Elevated Percentage of CD3+ T-Cells and CD4+/CD8+ Ratios in Multiple System Atrophy Patients

et al. 2020

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α-synuclein is involved in the pathogenesis of multiple system atrophy (MSA) and can be regulated by peripheral immune activation (PIA). We aimed to clarify the correlations between PIA and the prevalence of MSA and to analyze the role of PIA in the progression of the disease. A total of 321 patients with probable MSA and 321 age- and gender-matched healthy controls were included in this study. Lymphocyte subsets, including CD3 + , CD4 + , and CD8 + cells, and the levels of immunoglobulins IgG, IgM, and IgA were evaluated. The proportions of CD3 + and CD4 + T-lymphocytes were significantly increased in MSA patients compared with those of normal controls. In addition, the ratio of CD4 + to CD8 + cells was significantly increased in male MSA patients and IgG concentrations were decreased in female MSA patients. Furthermore, the concentrations of IgM in female MSA patients were dynamically different at various disease stages and gradually decreased from the early stage until the end stage of the disease ( p = 0.029). Other detected immunological indexes were not significantly different during the entire disease course. In this study, high proportions of CD3 + and CD4 + T-lymphocytes and decreased IgG levels were associated with an increased risk for MSA in a Chinese patient population. In addition, PIA may be involved in the progression of MSA.

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Section: Introductionmentioning

confidence: 99%

Elevated Percentage of CD3+ T-Cells and CD4+/CD8+ Ratios in Multiple System Atrophy Patients

et al. 2020

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“…Apart from the cardinal motor manifestations, non-motor symptoms (NMSs) can also be seen in over 50% of PD patients (Durcan et al, 2019). Although the underlying mechanism remains elusive, neuroinflammation is considered to be involved in α-syn transmission and dopaminergic neuronal degeneration (Hirsch and Hunot, 2009; Butkovich et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Peripheral Humoral Immune Response Is Associated With the Non-motor Symptoms of Parkinson’s Disease

Sun

Zhao

et al. 2019

Front. Neurosci.

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BackgroundNon-motor symptoms are common in Parkinson’s disease (PD) and can even be used as part of the supportive criteria for diagnosis. Chronic inflammation is involved in every stage of PD. Disorders of the immune system affect the peripheral blood. Whether the humoral immune response is associated with the non-motor symptoms of PD remains unknown.MethodsMann–Whitney tests and Bonferroni correction were used to compare the serum levels of IgG, IgA, IgM, C3, and C4 between 180 sporadic PD patients and 187 healthy controls. Multiple regression models were conducted to assess the associations among these indicators of humoral immunity and the clinical features of PD patients.ResultsMale PD patients had lower levels of C3 and C4 than healthy controls [0.87 (0.22) vs. 0.96 (0.19); 0.19 (0.06) vs. 0.22 (0.07), respectively, Pc < 0.01] and lower levels of C3 than female PD patients [0.87 (0.22) vs. 1.02 (0.23), Pc < 0.01]. Patients suffering from attention/memory problems had significantly lower levels of IgA and C3 than those without these problems [1.92 (1.21) vs. 2.57 (0.76); 0.89 (0.24) vs. 0.97 (0.24), respectively, Pc < 0.04]. In addition, serum IgG levels were negatively associated with mood/cognition problem scores and were positively associated with gastrointestinal tract problem scores (adjusted R2 = 0.063, F = 1.805, p = 0.038). Serum C3 levels were negatively associated with being male, age, and sleep/fatigue problem scores (adjusted R2 = 0.123, F = 2.678, p = 0.001).ConclusionThe peripheral humoral immune response might be correlated with the non-motor symptoms of PD.

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“…Thus, a multi-hit model has been proposed, in which the synergistic interaction between α-syn, dopamine and Ca 2+ in neurons may underlie neuronal loss in SNpc and LC (Post et al, 2018 ). Neurodegeneration in the LC may induce a direct loss of norepinephrine (NE), however, α-syn is also able to translocate to the nucleus of NE-producing cells and interfere with transcription of dopamine ß-hydroxylase, the final enzyme in NE biosynthesis, disrupting NE production and leading to a reduction of neurotrophic factor signaling, indirectly altering innate and adaptive immune response and worsening central and peripheral inflammation (Butkovich et al, 2018 ).…”

Section: α-Syn and Neurodegeneration: α-Synucleionopathiesmentioning

confidence: 99%

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

Heras‐Garvin

Stefanova

2020

Front. Synaptic Neurosci.

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Since its discovery 30 years ago, α-synuclein (α-syn) has been one of the most studied proteins in the field of neuroscience. Dozens of groups worldwide have tried to reveal not only its role in the CNS but also in other organs. α-syn has been linked to several processes essential in brain homeostasis such as neurotransmitter release, synaptic function, and plasticity. However, despite the efforts made in this direction, the main function of α-syn is still unknown. Moreover, α-syn became a protein of interest for neurologists and neuroscientists when mutations in its gene were found associated with Parkinson's disease (PD) and even more when α-syn protein deposits were observed in the brain of PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) patients. At present, the abnormal accumulation of α-syn constitutes one of the pathological hallmarks of these disorders, also referred to as α-synucleinopathies, and it is used for post-mortem diagnostic criteria. Whether α-syn aggregation is cause or consequence of the pathogenic events underlying α-synucleinopathies remains unclear and under discussion. Recently, different in vitro and in vivo studies have shown the ability of pathogenic α-syn to spread between cells, not only within the CNS but also from peripheral locations such as the gut, salivary glands, and through the olfactory network into the CNS, inducing abnormal misfolding of endogenous α-syn and leading to neurodegeneration and motor and cognitive impairment in animal models. Thus, it has been suggested that α-syn should be considered a prion protein. Here we present an update of what we know about α-syn function, aggregation and spreading, and its role in neurodegeneration. We also discuss the rationale and findings supporting the hypothetical prion nature of α-syn, its weaknesses, and future perspectives for research and the development of disease-modifying therapies.

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α-Synuclein and Noradrenergic Modulation of Immune Cells in Parkinson’s Disease Pathogenesis

Cited by 29 publications

References 201 publications

Elevated Percentage of CD3+ T-Cells and CD4+/CD8+ Ratios in Multiple System Atrophy Patients

Elevated Percentage of CD3+ T-Cells and CD4+/CD8+ Ratios in Multiple System Atrophy Patients

Peripheral Humoral Immune Response Is Associated With the Non-motor Symptoms of Parkinson’s Disease

From Synaptic Protein to Prion: The Long and Controversial Journey of α-Synuclein

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