Abstract
Deposition of α-synuclein into Lewy bodies and Lewy neurites is the hallmark of Parkinson’s disease (PD). It is hypothesized that α-synuclein pathology spreads by a “prion-like” mechanism (i.e., by seeded aggregation or templated misfolding). Therefore, various extracellular α-synuclein conformers and/or posttranslational modifications may serve as biomarkers of disease or potential targets for novel interventions. To explore whether the antibody repertoires of PD patients contain anti-α-synuclein antibodies that can potentially be used as markers or immunotherapy, we interrogated peripheral IgG+ memory B cells from PD patients for reactivity to α-synuclein. In total, ten somatically mutated antibodies were recovered, suggesting the presence of an ongoing antigen-driven immune response. The three antibodies that had the highest affinity to recombinant full-length α-synuclein, aSyn-323.1, aSyn-336.1 and aSyn-338.1, were characterized further and shown to recognize epitopes in the C terminus of α-synuclein with binding affinities between 0.3 and 2.8 μM. Furthermore, all three antibodies were able to neutralize the “seeding” of intracellular synuclein aggregates in an in vitro α-synuclein seeding assay. Finally, differential reactivities were observed for all three human anti-α-synuclein antibodies across tissue treatment conditions by immunohistochemistry. Our results suggest that the memory B-cell repertoire of PD patients might represent a potential source of biomarkers and therapies.
Highlights
Lewy bodies (LB) and Lewy neurites (LN), the neuropathological hallmarks of Parkinson’s disease (PD), are abnormal protein depositions generated by the misfolding and aggregation of α-synuclein, which is a natively disordered, 14 kD protein mostly localized to presynaptic terminals involved in vesicular transport
Blood samples from 25 PD patients were screened for the presence of memory B cells reactive to α-synuclein using our previously described BSelex method [30]
Certain posttranslational modifications (PTMs), alternative splicing, and truncations are associated with synuclein aggregation and neurotoxicity [6]
Summary
Lewy bodies (LB) and Lewy neurites (LN), the neuropathological hallmarks of Parkinson’s disease (PD), are abnormal protein depositions generated by the misfolding and aggregation of α-synuclein, which is a natively disordered, 14 kD protein mostly localized to presynaptic terminals involved in vesicular transport. Non-amyloid component (NAC) fragment of α-synuclein was found in amyloid-β (Aβ) plaques in Alzheimer’s disease (AD), and 50% of AD cases show Lewy Body pathology [10]. Α-synuclein has been suggested to regulate aggregation of Aβ [3] and tau [18], two proteins associated with neuropathological hallmarks of AD. Using human-induced pluripotent stem cells (hiPSC)-derived neurons and autologous co-culture with T cells, they demonstrated IL-17-mediated neuron death in PD patient-derived cell co-cultures [36]. These findings strongly support a critical role of adaptive immunity in PD
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