Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression
Introduction
How the immune system protects Parkinson's disease (PD) sufferers from toxic misfolded proteins requires resolution. It has been shown that α-synuclein protein, as a major PD biomarker (Lees et al., 2009) may be present not only as monomeric but also oligomeric forms in the substantia nigra or as aggregates in Lewy bodies (Yu and Lyubchenko, 2009). It has also been demonstrated that prefibrillar aggregates of α-synuclein, as well as other amyloid protein species, constitute generic toxins in higher organisms including humans (Baglioni et al., 2006). Correspondingly, El-Agnaf et al. (2006) reported raised levels of oligomeric forms of α-synuclein in PD patient plasma confirming α-synuclein misfolding during neurodegeneration in vivo. Furthermore, as an accompaniment to neurodegenerative processes, natural autoimmunity may well be perturbed by generation of toxic protein species in humans (Orr et al., 2005, Gruden et al., 2007, Roodveldt et al., 2008). Previously we found that peripheral immune responses to amyloid structures are a sensitive indicator of the early onset of neurodegenerative diseases (Gruden et al., 2004, Gruden et al., 2007). We have also evaluated autoimmune reactions to insulin amyloidogenic species as an endocrine biomarker in PD (Wilhelm et al., 2007). Moreover, it is a distinct possibility that dopamine (DA) released from degenerating neurons may influence the process of protein misfolding in PD (Pham et al., 2000). Immunological consequences associated with inflammation and oxidative stress have been proposed from the etiological pathogenic factors involved in the initial degenerative stages of parkinsonism (Czionkowska et al., 2002). One of these crucial factors is raised neurotrophin expression and stimulated release from cells by activated microglia. As a result, substantially increased concentrations of neurotrophins, for instance S100B, concurrently with toxic oligomeric species of α-synuclein continue to promote apoptosis and subsequent phagocytosis of DA neurons (Yu and Lyubchenko, 2009, Nagatsu et al., 2000, Rothermundt et al., 2003). In connection with this, it is possible that synchronized autoimmune responses towards elevated DA and neutrotrophic factors, in parallel with autoimmune reactions to toxic α-synuclein species, may also limit α-synuclein cytotoxicity. Therefore, the aim of this study is to ascertain any potential interrelationship between autoimmune responses to selected PD biomarkers and a range of other immune system parkinsonian parameters.
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Patients
PD patients (n = 32; 20 males and 12 females; 60.8 ± 2.0 years) were recruited from the Center of Neurology, RAMS. Patients underwent neurological examination and were diagnosed with PD according to disease severity by the UPDRS (Fahn and Elton, 1987). Patient scores ranged from 1 to 4, the majority being of grade 2 on the Hoehn and Yahr scale (Hoehn and Yahr, 1967). No opportunistic infections were observed either in PD patients or age-matched control subjects.
Both patient and control demographics
Characterization of α-synuclein oligomeric and fibrillar species
Oligomeric and fibrillar species of α-synuclein were characterized by the thioflavin-T binding assay and AFM analysis prior to ELISA. The formation of amyloid oligomers was accompanied by a 5 fold increase of thioflavin-T fluorescence (Fig. 1D), indicative of cross-β-sheet formation (Krebs et al., 2000). The oligomers were assessed by AFM as round-shapes (Fig. 1A) with heights 1.2–3.9 nm (Fig. 1B) and a maximal population centered around 1.8–2 nm corresponding to 20-mers [16]. The mature fibrils
Discussion
We simultaneously analyzed the spectrum of autoantibodies generated to native and amyloidogenic α-synuclein species, neurotrophic factor S100B and DA as major PD biomarkers in patient blood (Graeber, 2009) along with regulatory T- and B-cells. In altered conditions in vitro and in vivo, α-synuclein may self assemble forming ordered fibrils (Bertoncini et al., 2005) characterized by cross β-sheet structures similar to Lewy body aggregates (Foltynie et al., 2008). The initial phase of
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2022, Advances in Clinical ChemistryCitation Excerpt :In general, findings related to serum cortisol in PD are inconsistent. For example, serum cortisol was unchanged (four studies) [82,90,92,93] decreased (two studies) [87,94], or increased (six studies) in PD vs healthy controls or caregivers [83,85,91,95–97]. Interestingly, recent studies demonstrated increased cortisol in PD when a 24-h measurement was used [83,85].
T cells, α-synuclein and Parkinson disease
2022, Handbook of Clinical NeurologyCitation Excerpt :Patients with PD have fewer naive T cells (Bas et al., 2001; Saunders et al., 2012), including CD4+ Th (helper) cells (Bas et al., 2001; Calopa et al., 2010; Saunders et al., 2012), and more activated T cells (Chiba et al., 1995), including Th2 regulatory T cells (Tregs) (Bas et al., 2001; Calopa et al., 2010) than healthy age-matched controls. Some studies reported general decrease in total T cells (Baba et al., 2005; Calopa et al., 2010; Gruden et al., 2011), Tregs (Chen et al., 2015a; Kustrimovic et al., 2018), and CD8+ cytotoxic T cells (Gruden et al., 2011), whereas other studies show no change in Treg number (Rosenkranz et al., 2007) with an increase in Th1 cells and the Th17 subset in patients with PD (Chen et al., 2015b, 2017; Sommer et al., 2018). These disparate findings may be due to differences in phenotyping methods and patient recruitment.
Growing role of S100B protein as a putative therapeutic target for neurological- and nonneurological-disorders
2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In addition, the administration of the S100B inhibitor PTM resulted in a marked amelioration of motor performances in MPTP treated rats (Rinaldi et al., 2019). Intriguingly, it has been shown that S100B polymorphisms are associated with the age of PD onset (Fardell et al., 2018), while increased blood titers of autoantibodies to S100B have also been reported in PD patients (Gruden et al., 2011). The emerging role of S100B in PD pathogenesis has been addressed in a very recent and comprehensive review (Angelopoulou et al., 2020).