Abstract
Aggregation of alpha-synuclein (α-syn) is considered to be the major pathological hallmark and driving force of Multiple System Atrophy (MSA) and Parkinson's disease (PD). Immune dysfunctions have been associated with both MSA and PD and recently we reported that the levels of natural occurring autoantibodies (NAbs) with high-affinity/avidity toward α-synuclein are reduced in MSA and PD patients. Here, we aimed to evaluate the plasma immunoglobulin (Ig) composition binding α-syn and other amyloidogenic neuropathological proteins, and to correlate them with disease severity and duration in MSA and PD patients. All participants were recruited from a single neurological unit and the plasma samples were stored for later research at the Bispebjerg Movement Disorder Biobank. All patients were diagnosed according to current consensus criteria. Using multiple variable linear regression analyses, we observed higher levels of anti-α-syn IgG1 and IgG3 NAbs in MSA vs. PD, higher levels of anti-α-syn IgG2 NAbs in PD compared to controls, whereas anti-α-syn IgG4 NAbs were reduced in PD compared to MSA and controls. Anti-α-syn IgM levels were decreased in both MSA and PD. Further our data supported that MSA patients' immune system was affected with reduced IgG1 and IgM global levels compared to PD and controls, with further reduced global IgG2 levels compared to PD. These results suggest distinct autoimmune patterns in MSA and PD. These findings suggest a specific autoimmune physiological mechanism involving responses toward α-syn, differing in neurodegenerative disease with overlapping α-syn pathology.
Highlights
Multiple system atrophy (MSA) and Parkinson’s disease (PD) are neurodegenerative movement disorders which share many clinical and pathomorphological features [1, 2]
Anti-α-syn IgG2 levels described by disease group (p = 3.0E-04) were higher in PD compared to controls (p < 0.001; Figure 1C), as were the described anti-α-syn IgG4 levels by group (p = 3.5E-07), whereas anti-α-syn IgG4 was lower in PD compared to Multiple System Atrophy (MSA) and controls
Our model identified increased anti-Tau IgG1 levels in PD compared to MSA [F(4,125) = 5.0, p = 9.0E-04], only described by group (p = 1.0E-03) with decreased levels in MSA compared to PD (p = 0.022; Figure S1)
Summary
Multiple system atrophy (MSA) and Parkinson’s disease (PD) are neurodegenerative movement disorders which share many clinical and pathomorphological features [1, 2]. The pathological hallmark for these two diseases is the aggregation of the protein α-synuclein (α-syn), which precipitates as glial cytoplasmic inclusions in oligodendroglia in MSA and neuronal Lewy body inclusions in PD [1]. Α-syn is present in large amounts in the blood of both patients and healthy individuals and as inclusions in the enteric nervous system in PD [3, 4]. MSA is considered a sporadic disease of uncertain etiology, whereas at least 90% of PD cases are idiopathic and ∼10% represent rare Mendelian hereditary forms [1]. Discriminating between MSA and idiopathic PD can be difficult, especially at early stages, but usually MSA presents a more pernicious course. There is a need for more convenient and sensitive biomarkers for the disorder, which has great importance for prognostic measures and development of therapeutic strategies
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